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Dite GS, Wong CK, Gafni A, Spaeth E. Colorectal cancer risk prediction using a simple multivariable model. PLoS One 2025; 20:e0321641. [PMID: 40359298 PMCID: PMC12074527 DOI: 10.1371/journal.pone.0321641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 03/10/2025] [Indexed: 05/15/2025] Open
Abstract
Accurate population stratification of colorectal cancer risk enables identification of individuals who would benefit from screening and risk-reducing interventions. We conducted a population-based cohort study using almost 400,000 unaffected UK Biobank participants who were aged 40-69 years at their baseline assessment and who had genetically determined UK ancestry. For women and men separately, we developed (i) a multivariable risk prediction model using family history, a polygenic risk score (PRS) and clinical risk factors, and (ii) a simple model comprising family history and a PRS. We then compared their performance to that of existing models. The models were developed using Cox regression with age as the time axis in a 70% training dataset. The performance of the 10-year risk of colorectal cancer was assessed in a 30% testing dataset using Cox regression to estimate the hazard ratio per standard deviation of risk, Harrell's C-index to assess discrimination and logistic regression to assess calibration. There were 214,183 women and 181,889 men in the dataset with 1,913 women and 2,598 men diagnosed with colorectal cancer during the follow-up period. The mean age at diagnosis was 66.4 years (standard deviation = 7.3 years) for women and 67.3 years (standard deviation = 6.7 years) for men. In the 30% testing dataset, the new multivariable models discriminated better (Harrell's C-index = 0.690, 95% CI = 0.669 to 0.712 for women; 0.699, 95% CI = 0.681 to 0.717 for men) than the new family history and PRS models (Harrell's C-index = 0.683, 95% CI = 0.663 to 0.704 for women; 0.692, 95% CI = 0.673 to 0.710 for men; change in discrimination P = 0.02 for women and P = 0.01 for men). Our models identify individuals who are at increased risk of colorectal cancer and who would benefit from personalised screening and risk-reduction options.
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Affiliation(s)
| | - Chi Kuen Wong
- Genetic Technologies Limited, Fitzroy, Victoria, Australia
| | - Aviv Gafni
- Genetic Technologies Limited, Fitzroy, Victoria, Australia
| | - Erika Spaeth
- geneType Inc, Charlotte, North Carolina, United States of America
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Seum T, Cardoso R, Stevenson-Hoare J, Holleczek B, Schöttker B, Hoffmeister M, Brenner H. Exploring metabolomics for colorectal cancer risk prediction: evidence from the UK Biobank and ESTHER cohorts. BMC Med 2025; 23:283. [PMID: 40361100 PMCID: PMC12077020 DOI: 10.1186/s12916-025-04107-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND While metabolic pathway alterations are linked to colorectal cancer (CRC), the predictive value of pre-diagnostic metabolomic profiling in CRC risk assessment remains to be clarified. This study evaluated the predictive performance of a metabolomics risk panel (MRP) both independently and in combination with established risk factors. METHODS We derived, internally validated (IV), and externally validated (EV) a metabolomics risk panel (MRP) for CRC from data of the UK Biobank (UKB) and the German ESTHER cohort. Baseline blood samples were assessed for 249 metabolites using nuclear magnetic resonance spectroscopy analysis. We applied LASSO Cox proportional hazards regression to identify metabolites for inclusion in the MRP and evaluated the model performance using the concordance index (C-index). We compared the performance of the MRP to an environmental risk panel (ERP; sex, age, body mass index, smoking status, and alcohol consumption) and a genetic risk panel (GRP; polygenic risk score). RESULTS The study included 154,892 participants of the UKB cohort (mean age at baseline 54.5 years; 55.5% female) with 1879 incident CRC and 3242 participants of the ESTHER cohort (mean age 61.5 years; 52.2% female) with 103 CRC cases. Twenty-three metabolites, primarily amino acid and lipid-related metabolites, were selected for the MRP, showing moderate predictive performance (C-index 0.60 [IV] and 0.54 [EV]). The ERP and GRP showed superior performance, with C-index values of 0.73 (IV) and 0.69 (EV). Adding the MRP to these risk models did not change the C-indices in both cohorts. CONCLUSIONS Genetic and environmental risk information provided strong predictive accuracy for CRC risk, with no improvements from adding metabolomics data. These findings suggest that metabolomics data may have limited impact on enhancing established CRC risk models in clinical practice.
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Affiliation(s)
- Teresa Seum
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany
- Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, Heidelberg, 69120, Germany
| | - Rafael Cardoso
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany
| | - Joshua Stevenson-Hoare
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany
| | - Bernd Holleczek
- Saarland Cancer Registry, Präsident-Baltz-Strasse 5, Saarbrücken, 66119, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany.
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany, 69120.
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Huang X, Ren S, Mao X, Chen S, Chen E, He Y, Jiang Y. Association Between Risk Factors and Major Cancers: Explainable Machine Learning Approach. JMIR Cancer 2025; 11:e62833. [PMID: 40315870 PMCID: PMC12064211 DOI: 10.2196/62833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 03/08/2025] [Accepted: 03/20/2025] [Indexed: 05/04/2025] Open
Abstract
Background Cancer is a life-threatening disease and a leading cause of death worldwide, with an estimated 611,000 deaths and over 2 million new cases in the United States in 2024. The rising incidence of major cancers, including among younger individuals, highlights the need for early screening and monitoring of risk factors to manage and decrease cancer risk. Objective This study aimed to leverage explainable machine learning models to identify and analyze the key risk factors associated with breast, colorectal, lung, and prostate cancers. By uncovering significant associations between risk factors and these major cancer types, we sought to enhance the understanding of cancer diagnosis risk profiles. Our goal was to facilitate more precise screening, early detection, and personalized prevention strategies, ultimately contributing to better patient outcomes and promoting health equity. Methods Deidentified electronic health record data from Medical Information Mart for Intensive Care (MIMIC)-III was used to identify patients with 4 types of cancer who had longitudinal hospital visits prior to their diagnosis presence. Their records were matched and combined with those of patients without cancer diagnoses using propensity scores based on demographic factors. Three advanced models, penalized logistic regression, random forest, and multilayer perceptron (MLP), were conducted to identify the rank of risk factors for each cancer type, with feature importance analysis for random forest and MLP models. The rank biased overlap was adopted to compare the similarity of ranked risk factors across cancer types. Results Our framework evaluated the prediction performance of explainable machine learning models, with the MLP model demonstrating the best performance. It achieved an area under the receiver operating characteristic curve of 0.78 for breast cancer (n=58), 0.76 for colorectal cancer (n=140), 0.84 for lung cancer (n=398), and 0.78 for prostate cancer (n=104), outperforming other baseline models (P<.001). In addition to demographic risk factors, the most prominent nontraditional risk factors overlapped across models and cancer types, including hyperlipidemia (odds ratio [OR] 1.14, 95% CI 1.11-1.17; P<.01), diabetes (OR 1.34, 95% CI 1.29-1.39; P<.01), depressive disorders (OR 1.11, 95% CI 1.06-1.16; P<.01), heart diseases (OR 1.42, 95% CI 1.32-1.52; P<.01), and anemia (OR 1.22, 95% CI 1.14-1.30; P<.01). The similarity analysis indicated the unique risk factor pattern for lung cancer from other cancer types. Conclusions The study's findings demonstrated the effectiveness of explainable ML models in assessing nontraditional risk factors for major cancers and highlighted the importance of considering unique risk profiles for different cancer types. Moreover, this research served as a hypothesis-generating foundation, providing preliminary results for future investigation into cancer diagnosis risk analysis and management. Furthermore, expanding collaboration with clinical experts for external validation would be essential to refine model outputs, integrate findings into practice, and enhance their impact on patient care and cancer prevention efforts.
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Affiliation(s)
- Xiayuan Huang
- Department of Biostatistics, Yale University, New Haven, CT, United States
| | - Shushun Ren
- School of Nursing, University of Michigan–Ann Arbor, 400 North Ingalls Street, Ann Arbor, MI, 48109, United States, 1 7347633705, 1 7346472416
| | - Xinyue Mao
- College of Literature Science and the Arts, University of Michigan–Ann Arbor, Ann Arbor, MI, United States
| | - Sirui Chen
- College of Literature Science and the Arts, University of Michigan–Ann Arbor, Ann Arbor, MI, United States
| | - Elle Chen
- School of Nursing, University of Michigan–Ann Arbor, 400 North Ingalls Street, Ann Arbor, MI, 48109, United States, 1 7347633705, 1 7346472416
| | - Yuqi He
- University Library, San Jose State University, San Jose, CA, United States
| | - Yun Jiang
- School of Nursing, University of Michigan–Ann Arbor, 400 North Ingalls Street, Ann Arbor, MI, 48109, United States, 1 7347633705, 1 7346472416
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Wu C, Zhou J, Wu Q, Xu S, Jiang J, Li S, Chen X. Colorectal Cancer Risk Loci: Prognostic Factors for Clinical Outcomes? A Systematic Review and Meta-Analysis. Cancer Rep (Hoboken) 2025; 8:e70230. [PMID: 40387276 DOI: 10.1002/cnr2.70230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 04/08/2025] [Accepted: 05/04/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Several single nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWASs) on colorectal cancer (CRC) incidence are also shown as promising predictors of clinical outcomes in CRC patients. These genetic variants might help inform precision prognostic strategies by predicting disease progression, treatment response, and overall survival, thereby guiding more personalized treatment plans. However, conflicting evidence exists regarding their clinical relevance. AIM A systematic review and meta-analysis was performed to assess the potential of GWAS-identified SNPs in predicting CRC outcomes. METHODS AND RESULTS We conducted a comprehensive search of PubMed, Web of Science, Embase, and Cochrane databases up to 18 October 2024 for prospective studies that investigated the associations of CRC-related SNPs and polygenic risk scores (PRSs) built based on multiple SNPs with clinical outcomes. Quality of the included studies was assessed using the Newcastle-Ottawa Scale, and the heterogeneity was assessed by I2 index and Cochran's Q test. The final analysis included 22 studies with overall high quality and heterogeneity in several aspects (e.g., genetic models, ethnic background, and genetic signatures of CRC types). Among over 100 CRC risk-related loci, 12 SNPs were statistically associated with CRC clinical outcomes (mainly survival outcomes), which were replicated in multiple studies. Notably, rs9929218 and rs6983267, located in genes involved in processes of tumorigenesis, were linked to poor survival with hazard ratios (95% CIs) of 1.26 (1.12-1.42) under a recessive model and 1.33 (1.10-1.61) under an additive model, respectively, in the stratified analysis by genetic models. Besides, PRSs built based on survival-related SNPs were moderately associated with overall survival in CRC patients with hazard ratios exceeding 2.6 for each one-point increase in PRS. CONCLUSIONS Individual genetic variants and PRSs are predictive of CRC survival, and might serve as potential factors for risk stratification, which could help develop personalized treatment and surveillance strategies for CRC patients. However, the potential for false positives and the significant heterogeneity among studies that cannot be fully addressed in the current analysis due to limited data require a cautious interpretation of these findings. Large-scale studies are warranted to further explore and validate GWAS-identified SNPs for promising prognostic biomarkers in CRC patients while accounting for factors such as ethnic differences and tumor subtypes.
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Affiliation(s)
- Chengmi Wu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jingyi Zhou
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Qian Wu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Shu Xu
- Department of Oncology, Shenzhen Guangming District People's Hospital, Shenzhen, China
| | - Jie Jiang
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Sha Li
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Xuechen Chen
- College of Pharmacy, Jinan University, Guangzhou, China
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Chiu HM, Matsuda T. Adopting Non-invasive Approaches into Precision Colorectal Cancer Screening. Dig Dis Sci 2025; 70:1616-1624. [PMID: 39516436 DOI: 10.1007/s10620-024-08696-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024]
Abstract
Effective screening is essential to reducing CRC incidence and mortality by detecting the disease at early stages and identifying non-invasive precursors. While colonoscopy remains the most sensitive modality to visualize and remove neoplastic lesions thereby reducing CRC and the related death, its high cost and invasive nature limit its widespread use. The fecal immunochemical test (FIT), which offers a non-invasive alternative with higher public acceptance and comparable cost-effectiveness to colonoscopy, has become the preferred screening method in many regions. Newer non-invasive tests, such as multitarget stool DNA or RNA tests, have shown improved sensitivity for CRC and advanced adenomas, although their high costs and lower specificity present challenges for large-scale implementation. Blood-based circulating cell-free DNA test also offer promise but still require optimization to be cost-effective. The heterogeneity of the screening population further complicates the effectiveness of CRC screening programs. Variations in non-communicable disease risk factors, such as metabolic syndrome, lifestyle habits, and comorbidities, can significantly influence CRC risk and screening outcomes. Moreover, diverse screening behaviors, including inconsistent adherence to recommended screening intervals and the interchangeable use of different screening modalities, add complexity to achieving uniform effectiveness across populations. This variability underscores the need for personalized screening strategies that consider individual risk profiles and screening behaviors, as well as the application of cutting-edge technologies such as big data analytics, artificial intelligence, and digital twin approaches to evaluate its effectiveness. This article reviews the current CRC screening strategies, the advantages of non-invasive methods, and the potential of fecal hemoglobin concentration, to tailor screening intervals and improve risk stratification. It also discusses the emerging role of real-world data and advanced technologies in enhancing CRC screening accuracy and effectiveness, particularly in complex real-world scenarios where traditional methods may fall short. Before novel non-invasive approaches, such as ctDNA tests or polygenic risk scores, are validated and proven cost-effective, exploring the clinical utility of FIT and its quantitative measurement in both screening and surveillance by integrating real-world clinical big data seems a feasible direction for achieving sustained development in population screening.
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Affiliation(s)
- Han-Mo Chiu
- Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.
| | - Takahisa Matsuda
- Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
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Hu FL, Liu JC, Li DR, Xu YL, Liu BQ, Chen X, Zheng WR, Wei YF, Liu FH, Li YZ, Xu HL, Cao F, Ma MX, Gong TT, Wu QJ. EAT-Lancet diet pattern, genetic risk, and risk of colorectal cancer: a prospective study from the UK Biobank. Am J Clin Nutr 2025; 121:1017-1024. [PMID: 39993568 DOI: 10.1016/j.ajcnut.2025.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/11/2025] [Accepted: 02/19/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Diet and genetic risk are risk factors for colorectal cancer (CRC). The interaction between the EAT (Lancet Commission on healthy diets from sustainable food systems)-Lancet diet and genetic variants on CRC risk remains unclear. OBJECTIVES We aim to investigate the association between EAT-Lancet diet and CRC risk and to evaluate its combined effect with genetic risk on CRC risk. METHODS We conducted a prospective cohort study involving 177,441 participants from the UK Biobank who completed 24-h food recall questionnaires at least once. The EAT-Lancet Diet Index (ELD-I) was calculated using the dietary recall data to assess EAT-Lancet diet, and a polygenic risk score (PRS) was constructed by using 197 single-nucleotide polymorphisms to evaluate genetic risk. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models to assess the associations. RESULTS During a median follow-up of 13.05 y, 2,016 participants developed CRC. Higher ELD-I was significantly associated with a reduced CRC risk (the highest compared with the lowest HR: 0.87, 95% CI: 0.76-0.99). A significant additive interaction between PRS and ELD-I was identified on CRC risk (relative excess risk due to interaction: 0.142, 95% CI: 0.058, 0.225). The ELD-I was significantly associated with reduced CRC risk in individuals with moderate but not low and high genetic risk, with HRs (95% CIs) of 0.76 (0.63, 0.92), 0.84 (0.53, 1.33), and 0.96 (0.76, 1.20), respectively. Compared with participants with higher PRS and lower ELD-I, those with lower PRS and higher ELD-I showed a 75% reduction in CRC risk (HR: 0.25; 95% CI: 0.17, 0.36). CONCLUSIONS The ELD-I could reduce 13% of CRC risk, especially in individuals with a moderate genetic risk. Individuals with high ELD-I and low PRS had the lowest CRC risk than those with low ELD-I and high PRS. These findings underscore the potential role of EAT-Lancet Diet in CRC prevention.
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Affiliation(s)
- Fu-Lan Hu
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Jia-Cheng Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Dong-Run Li
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Lin Xu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Bang-Quan Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xi Chen
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Wen-Rui Zheng
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Fan Wei
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fang-Hua Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Zi Li
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - He-Li Xu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fan Cao
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ming-Xing Ma
- Department of Colorectal Cancer Surgery, Shengjing Hospital of China Medical University, Shenyang, China; Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Ting-Ting Gong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qi-Jun Wu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China; Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China; NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China.
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Sandhu S, Blandon C, Kumar S. Evaluating Risk Factors for Early-Onset Colorectal Cancer in a Large, Prospective Cohort. Dig Dis Sci 2025:10.1007/s10620-025-09055-2. [PMID: 40234296 DOI: 10.1007/s10620-025-09055-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 04/09/2025] [Indexed: 04/17/2025]
Abstract
BACKGROUND Despite the worrisome rise of early-onset colorectal cancer (EOCRC), risk factors have not been definitively established. We use a large, granular database to evaluate risk factors for EOCRC, investigate differences in associations with EOCRC and later-onset CRC (LOCRC), and compare metrics of accelerated aging, a hypothesized driver of EOCRC. METHODS This was a case-control analysis within the UK Biobank. Risk factors for each cancer were identified and compared, including aging measures (chronological age, telomere length, PhenoAge, and homeostatic dysregulation). RESULTS A total of 31,164 persons were matched. We found an increased risk of EOCRC with PRS (OR 1.53; 95% CI 1.19-1.97; p < 0.001). LOCRC was associated with increasing PRS (OR 1.48; 95% CI 1.44 - 1.53; p < 0.001), increasing waist-to-hip ratio (OR 5.81; 95% CI 3.25 - 10.38; p < 0.001), family history of CRC (OR 1.27; 95% CI 1.16 - 1.40; p < 0.001), and history of smoking (OR 1.11; 95% CI 1.03 - 1.19; p = 0.01). Male sex and prior CRC screening were associated with reduced risk of LOCRC. The inclusion of PhenoAge as the measure of aging demonstrated the best model fit for both EOCRC and LOCRC. For each year that PhenoAge exceeded chronological age, the odds of EOCRC increased by 7%, while odds of LOCRC only increased by 1%. CONCLUSIONS Within this study, we find that genetic risk variants are a significant driver of EOCRC risk. Accelerated aging appears to be associated with increased risk of both EOCRC and LOCRC, and measures such as PhenoAge warrant continued study.
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Affiliation(s)
- Sunny Sandhu
- Division of Digestive Health and Liver Diseases, Department of Medicine, Miller School of Medicine at the University of Miami, 1120 NW 14th St, Locator Code C-240, Miami, FL, 33136, USA
| | - Catherine Blandon
- Division of Digestive Health and Liver Diseases, Department of Medicine, Miller School of Medicine at the University of Miami, 1120 NW 14th St, Locator Code C-240, Miami, FL, 33136, USA
| | - Shria Kumar
- Division of Digestive Health and Liver Diseases, Department of Medicine, Miller School of Medicine at the University of Miami, 1120 NW 14th St, Locator Code C-240, Miami, FL, 33136, USA.
- Sylvester Comprehensive Cancer Center, Miller School of Medicine at the University of Miami, 1120 NW 14th St, Locator Code C-240, Miami, FL, 33136, USA.
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Yun D, Yang JH, Yang S, Sim JA, Kim M, Park JW, Jeong SY, Shin A, Kweon SS, Song N. Novel genetic loci and functional properties of immune-related genes for colorectal cancer survival in Korea. BMC Cancer 2025; 25:456. [PMID: 40082818 PMCID: PMC11905532 DOI: 10.1186/s12885-025-13819-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 02/26/2025] [Indexed: 03/16/2025] Open
Abstract
One major topic in colorectal cancer (CRC) research is the role of immune cells against cancer cells. The association of single-nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) with CRC was examined and their functional properties were identified using a gene-gene interaction network. 960 CRC patients at Seoul National University Hospital (SNUH, discovery) and 6,627 CRC patients at Chonnam National University Hospital (CNNUH, validation) were enrolled. SNPs were genotyped using the Korean Biobank Array. 2,729 immune-related genes were selected from the Ensembl, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes, and 37,398 SNPs were mapped. PRS were categorized into tertiles. Cox proportional hazard models were fitted for overall survival (OS) and progression-free survival (PFS). A gene-gene interaction network was analyzed. Among CRC patients from SNUH, 154 (16.0%) died, while 245 (25.5%) had progression. In CNNUH, 3,537 (53.4%) died. For OS, the most significant association was observed for rs117322760 (8q23.1, PKHD1L1, hazard ratio (HR) = 4.58, p-value = 1.40 × 10- 6). For PFS, it was observed in rs143531681 (7q36.1, NOS3, HR = 4.67, p-value = 9.72 × 10- 8). For PRS, the highest tertile group showed an increased risk for OS (HR = 59.58, p-value = 9.20 × 10-48) and PFS (HR = 9.81, p-value = 1.69 × 10-23). Significant interactions were observed between PIK3R2 and PIK3CA for OS and ALOX5 and COTL1 for PFS. This study presented novel genetic variants associated with OS and PFS in CRC patients, and notable findings from the analysis of PRS and the gene-gene interaction.
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Affiliation(s)
- Dabin Yun
- College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Jung-Ho Yang
- Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Jeonnam, Korea
| | - Soyoun Yang
- College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Jin-Ah Sim
- Department of AI Convergence, Hallym University, Chuncheon, Gangwon, Korea
| | - Minjung Kim
- Department of Surgery, College of Medicine and Hospital, Seoul National University, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Ji Won Park
- Department of Surgery, College of Medicine and Hospital, Seoul National University, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Seung Yong Jeong
- Department of Surgery, College of Medicine and Hospital, Seoul National University, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Aesun Shin
- Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Korea
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Jeonnam, Korea
| | - Nan Song
- College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, Korea.
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Fu R, Chen X, Seum T, Hoffmeister M, Brenner H. Alcohol consumption, polygenic risk score, and the risk of colorectal neoplasia. JNCI Cancer Spectr 2025; 9:pkaf017. [PMID: 39898811 PMCID: PMC11901593 DOI: 10.1093/jncics/pkaf017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/16/2025] [Accepted: 01/26/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Excess alcohol consumption is associated with increased risk of colorectal cancer, but the evidence on the individual and joint effects of alcohol consumption and genetic risk on the occurrence of various stages of colorectal carcinogenesis is limited. METHODS We evaluated the associations of alcohol consumption and a polygenic risk score based on 140 colorectal cancer related loci with findings of colorectal neoplasia among 4662 participants in the German screening colonoscopy program. Analyses were conducted by multiple logistic regression. We determined genetic risk equivalents to quantify the effect of alcohol consumption in terms of the difference in polygenic risk score conveying equivalent risk. RESULTS Moderate and high (12 to <25 g/d and ≥25 g/d) alcohol consumption was associated with increased risk of advanced colorectal neoplasia (adjusted odds ratio = 1.28, 95% CI = 1.03 to 1.58, and adjusted odds ratio = 1.44, 95% CI = 1.14 to 1.81, respectively), while associations with any colorectal neoplasia were weaker. No significant interactions between alcohol consumption and polygenic risk score were observed. Participants with high alcohol consumption in the highest polygenic risk score tertile had a 3.4-fold increased risk of advanced neoplasia compared with individuals with low or no alcohol consumption in the lowest polygenic risk score tertile. The estimated impact of high alcohol consumption on the risk of advanced neoplasia was equivalent to the risk increase by a 26-percentile-higher polygenic risk score (genetic risk equivalent = 26, 95% CI = 9 to 44). CONCLUSION High alcohol consumption and polygenic risk score have a major impact on the risk of advanced colorectal neoplasia. The estimated preventive impact of avoiding high alcohol consumption is as strong as the impact of having a substantially lower polygenic risk.
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Affiliation(s)
- Ruojin Fu
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg 69120, Germany
| | - Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
- College of Pharmacy, Jinan University, Guangzhou 511436, China
| | - Teresa Seum
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg 69120, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
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10
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Guo B, Cai Y, Kim D, Smit RAJ, Wang Z, Iyer KR, Hilliard AT, Haessler J, Tao R, Broadaway KA, Wang Y, Pozdeyev N, Stæger FF, Yang C, Vanderwerff B, Patki AD, Stalbow L, Lin M, Rafaels N, Shortt J, Wiley L, Stanislawski M, Pattee J, Davis L, Straub PS, Shuey MM, Cox NJ, Lee NR, Jørgensen ME, Bjerregaard P, Larsen C, Hansen T, Moltke I, Meigs JB, Stram DO, Yin X, Zhou X, Chang KM, Clarke SL, Guarischi-Sousa R, Lankester J, Tsao PS, Buyske S, Graff M, Raffield LM, Sun Q, Wilkens LR, Carlson CS, Easton CB, Liu S, Manson JE, Marchand LL, Haiman CA, Mohlke KL, Gordon-Larsen P, Albrechtsen A, Boehnke M, Rich SS, Manichaikul A, Rotter JI, Yousri NA, Irvin RM, Gignoux C, North KE, Loos RJF, Assimes TL, Peters U, Kooperberg C, Raghavan S, Highland HM, Darst BF. Type 2 diabetes polygenic risk score demonstrates context-dependent effects and associations with type 2 diabetes-related risk factors and complications across diverse populations. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.15.25322341. [PMID: 40034751 PMCID: PMC11875254 DOI: 10.1101/2025.02.15.25322341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Polygenic risk scores (PRS) hold prognostic value for identifying individuals at higher risk of type 2 diabetes (T2D). However, further characterization is needed to understand the generalizability of T2D PRS in diverse populations across various contexts. We characterized a multi-ancestry T2D PRS among 244,637 cases and 637,891 controls across eight populations from the Population Architecture Genomics and Epidemiology (PAGE) Study and 13 additional biobanks and cohorts. PRS performance was context dependent, with better performance in those who were younger, male, with a family history of T2D, without hypertension, and not obese or overweight. Additionally, the PRS was associated with various diabetes-related cardiometabolic traits and T2D complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between T2D and other diseases. These findings highlight the need to account for context when evaluating PRS as a tool for T2D risk prognostication and potentially generalizable associations of T2D PRS with diabetes-related traits despite differential performance in T2D prediction across diverse populations.
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11
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Shen Y, Chen W, Fu C, Liu X, Miao J, Li J, Li N, Hang D. Polygenic Risk Score, Healthy Lifestyle Score, and Colorectal Cancer Risk: A Prospective Cohort Study. Cancer Epidemiol Biomarkers Prev 2025; 34:290-297. [PMID: 39570087 DOI: 10.1158/1055-9965.epi-24-1013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/24/2024] [Accepted: 11/19/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Both genetic factors and lifestyle play a critical role in colorectal cancer, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unclear. METHODS We included 51,171 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer cohort. A polygenic risk score was created based on 205 genetic variants associated with colorectal cancer, and a healthy lifestyle score was constructed based on six lifestyle factors. Cox regression models were used to evaluate the association of genetic and lifestyle factors with colorectal cancer incidence. RESULTS Compared with individuals at low genetic risk (the lowest 20%), those with intermediate genetic risk (20%-80%) and high genetic risk (the highest 20%) had a significantly increased risk of colorectal cancer (HR = 1.71 and 2.52, respectively). Compared with participants with a favorable lifestyle (scoring 4-6), those with an unfavorable lifestyle (scoring 0 or 1) had a 47% higher risk of colorectal cancer. Moreover, participants with a high genetic risk and a favorable lifestyle had a 45% lower risk of colorectal cancer than those with a high genetic risk and an unfavorable lifestyle, with their 10-year absolute risks of 1.29% and 2.07%, respectively. CONCLUSIONS Our findings suggest that adherence to a healthy lifestyle holds promise to reduce the genetic impact on colorectal cancer risk. IMPACT This study indicates that modifiable lifestyle factors play an important role in colorectal cancer prevention, providing new insights for personalized prevention strategies.
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Affiliation(s)
- Yuefan Shen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weiwei Chen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chengqu Fu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xinyi Liu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Junyan Miao
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiacong Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ni Li
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dong Hang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and International Joint Research Center on Environment and Human Health, Nanjing Medical University, Nanjing, China
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12
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Kim J, Kang JH, Wiggs JL, Zhao H, Li K, Zebardast N, Segrè A, Friedman DS, Do R, Khawaja AP, Aschard H, Pasquale LR. Does Age Modify the Relation Between Genetic Predisposition to Glaucoma and Various Glaucoma Traits in the UK Biobank? Invest Ophthalmol Vis Sci 2025; 66:57. [PMID: 39982391 PMCID: PMC11855177 DOI: 10.1167/iovs.66.2.57] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 01/15/2025] [Indexed: 02/22/2025] Open
Abstract
Purpose Glaucoma polygenic risk scores could guide glaucoma public health screening initiatives. We investigated how age influences the relationship between a multitrait glaucoma polygenic risk score (mtGPRS) and primary open-angle glaucoma indicators, including intraocular pressure (IOP), retinal structure, and glaucoma prevalence. Methods We analyzed UK Biobank participants with demographic and genetic data, assessing IOP (n = 118,153), macular retinal nerve fiber layer thickness (mRNFL; n = 42,132), macular ganglion cell inner plexiform layer thickness (mGCIPL; n = 42,042), and prevalent glaucoma status (8982 cases among 192,283 participants). An mtGPRS was constructed using 2673 genetic variants. We used multivariable linear regression to assess how age modifies the relationship between mtGPRS and glaucoma traits (IOP, mRFNL, and mGCIPL) and multivariable logistic regression for prevalent glaucoma risk. We analyzed age quartiles (Q1 = <51, Q2 = 51-57, Q3 = 58-62, and Q4 = ≥63 years) - glaucoma trait interaction tests with the Wald test. All analyses were adjusted for confounders, including nonlinear age effects. Results Age significantly modified the relationship between the mtGPRS and IOP (Pinteraction = 2.7e-27). Mean IOP differences (millimeters of mercury [mm Hg]) per standard deviation (SD) of mtGPRS were 0.95, 1.02, 1.18, and 1.24 across age quartiles. Similar trends were observed for glaucoma risk (odds ratio per SD of mtGPRS = 2.38, 2.57, 2.80, and 2.75; Pinteraction = 1.0e-06). Relationships between mtGPRS and inner retinal thickness (mRNFL and mGCIPL) across age strata were inconsistently modified by age (Pinteraction ≥ 0.01). Conclusions With increasing age, an mtGPRS was a better predictor of higher IOP and glaucoma prevalence. It is useful to consider chronological age with genetic information in designing glaucoma screening strategies.
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Affiliation(s)
- Jihye Kim
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States
| | - Jae H. Kang
- Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
| | - Janey L. Wiggs
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
| | - Hetince Zhao
- Department of Ophthalmology, Icahn School of Medicine, Mount Sinai, New York, New York, United States
| | - Keva Li
- Department of Ophthalmology, Icahn School of Medicine, Mount Sinai, New York, New York, United States
| | - Nazlee Zebardast
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
| | - Ayellet Segrè
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
| | - David S. Friedman
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
| | - Ron Do
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Anthony P. Khawaja
- NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, England, United Kingdom
| | - Hugues Aschard
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States
- Institut Pasteur, Université de Paris, Department of Computational Biology, Paris, France
| | - Louis R. Pasquale
- Department of Ophthalmology, Icahn School of Medicine, Mount Sinai, New York, New York, United States
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13
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Ji C, Ge W, Zhu C, Shen F, Yu Y, Pang G, Li Q, Zhu M, Ma Z, Zhu X, Fu Y, Gong L, Wang T, Du L, Jin G, Zhu M. Family history and genetic risk score combined to guide cancer risk stratification: A prospective cohort study. Int J Cancer 2025; 156:505-517. [PMID: 39291673 DOI: 10.1002/ijc.35187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 07/18/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024]
Abstract
Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.
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Affiliation(s)
- Chen Ji
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Wenjing Ge
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Chen Zhu
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Fang Shen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Yuhui Yu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Guanlian Pang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Qiao Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Mingxuan Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Zhimin Ma
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Xia Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Yating Fu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Linnan Gong
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Tianpei Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Lingbin Du
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
- Public Health Institute of Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
- The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
- Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing, China
| | - Meng Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
- The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
- Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing, China
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14
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Goldberg SR, Ko LK, Hsu L, Yin H, Kooperberg C, Peters U, Burnett-Hartman AN. Patient Perspectives on Personalized Risk Communication Using Polygenic Risk Scores to Inform Colorectal Cancer Screening Decisions. AJPM FOCUS 2025; 4:100308. [PMID: 39866161 PMCID: PMC11761838 DOI: 10.1016/j.focus.2024.100308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Introduction Colorectal cancer is increasingly diagnosed in people aged <50 years. New U.S. guidelines recommend screening initiation at age 45 years. Providing personalized risk for colorectal cancer using polygenic risk scores may be an opportunity to engage this younger population in colorectal cancer screening. There is limited research on patient understanding of polygenic risk scores results and use of polygenic risk scores to inform colorectal cancer screening decisions. Methods From May 2022 to June 2023, 20 Kaiser Permanente Colorado members aged 46-51 years who had been offered colorectal cancer screening but had never completed it signed consent to provide a saliva sample for colorectal cancer polygenic risk score analysis. After receiving personalized polygenic risk scores for colorectal cancer, participants completed a semistructured interview regarding the understanding of their polygenic risk scores, perceived colorectal cancer risk, and intention to screen. Thematic analysis was conducted using Atlas.ti, Version 8. Results Of the 19 participants who successfully completed polygenic risk score-related testing and a semistructured interview, 13 were female, 14 never smoked cigarettes, 6 were Hispanic, and 13 were non-Hispanic White. One participant had high risk for colorectal cancer on the basis of polygenic risk score results. Qualitative interviews showed participants' understanding of their results, trust in polygenic risk scores, perception of risk for colorectal cancer, plans to complete colorectal cancer screening, intent to share polygenic risk scores with healthcare providers, and concerns about genetic results impacting health care. Conclusions Qualitative analyses suggest that participants were interested in and understood their polygenic risk score results. Further study is needed to develop guidelines, effective calls to action, provider engagement, and health education materials on use of polygenic risk scores for health decision making.
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Affiliation(s)
- Shauna R. Goldberg
- Kaiser Permanente Colorado Institute for Health Research, Aurora, Colorado
| | - Linda K. Ko
- Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Health Systems and Population Health, University of Washington, Seattle, Washington
| | - Li Hsu
- Fred Hutchinson Cancer Center, Seattle, Washington
| | - Hang Yin
- Fred Hutchinson Cancer Center, Seattle, Washington
| | | | | | - Andrea N. Burnett-Hartman
- Kaiser Permanente Colorado Institute for Health Research, Aurora, Colorado
- Fred Hutchinson Cancer Center, Seattle, Washington
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15
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Hechtman JF, Baskovich B, Fussell A, Geiersbach KB, Iorgulescu JB, Sirohi D, Snow A, Sidiropoulos N. Charting the Genomic Frontier: 25 Years of Evolution and Future Prospects in Molecular Diagnostics for Solid Tumors. J Mol Diagn 2025; 27:6-11. [PMID: 39722285 DOI: 10.1016/j.jmoldx.2024.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/09/2024] [Accepted: 08/22/2024] [Indexed: 12/28/2024] Open
Affiliation(s)
- Jaclyn F Hechtman
- Solid Tumors Subdivision Leadership of the Association for Molecular Pathology, Rockville, Maryland; Caris Life Sciences, Irving, Texas.
| | - Brett Baskovich
- Solid Tumors Subdivision Leadership of the Association for Molecular Pathology, Rockville, Maryland; Mount Sinai Health System, New York, New York
| | - Amber Fussell
- The Association for Molecular Pathology, Rockville, Maryland
| | - Katherine B Geiersbach
- Solid Tumors Subdivision Leadership of the Association for Molecular Pathology, Rockville, Maryland; Mayo Clinic, Rochester, Minnesota
| | - J Bryan Iorgulescu
- Solid Tumors Subdivision Leadership of the Association for Molecular Pathology, Rockville, Maryland; Molecular Diagnostics Laboratory, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Deepika Sirohi
- Solid Tumors Subdivision Leadership of the Association for Molecular Pathology, Rockville, Maryland; University of California San Francisco, San Fransico, California
| | - Anthony Snow
- Solid Tumors Subdivision Leadership of the Association for Molecular Pathology, Rockville, Maryland; University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - Nikoletta Sidiropoulos
- Solid Tumors Subdivision Leadership of the Association for Molecular Pathology, Rockville, Maryland; University of Vermont Medical Group, Burlington, Vermont
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16
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Rosenthal EA, Hsu L, Thomas M, Peters U, Kachulis C, Patterson K, Jarvik GP. Comparing Ancestry Standardization Approaches for a Transancestry Colorectal Cancer Polygenic Risk Score. Genet Epidemiol 2025; 49:e22590. [PMID: 39315597 DOI: 10.1002/gepi.22590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/01/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024]
Abstract
Colorectal cancer (CRC) is a complex disease with monogenic, polygenic and environmental risk factors. Polygenic risk scores (PRSs) aim to identify high polygenic risk individuals. Due to differences in genetic background, PRS distributions vary by ancestry, necessitating standardization. We compared four post-hoc methods using the All of Us Research Program Whole Genome Sequence data for a transancestry CRC PRS. We contrasted results from linear models trained on A. the entire data or an ancestrally diverse subset AND B. covariates including principal components of ancestry or admixture. Standardization with the training subset also adjusted the variance. All methods performed similarly within ancestry, OR (95% C.I.) per s.d. change in PRS: African 1.5 (1.02, 2.08), Admixed American 2.2 (1.27, 3.85), European 1.6 (1.43, 1.89), and Middle Eastern 1.1 (0.71, 1.63). Using admixture and an ancestrally diverse training set provided distributions closest to standard Normal. Training a model on ancestrally diverse participants, adjusting both the mean and variance using admixture as covariates, created standard Normal z-scores, which can be used to identify patients at high polygenic risk. These scores can be incorporated into comprehensive risk calculation including other known risk factors, allowing for more precise risk estimates.
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Affiliation(s)
- Elisabeth A Rosenthal
- Division Medical Genetics, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Minta Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | - Karynne Patterson
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA
| | - Gail P Jarvik
- Division Medical Genetics, School of Medicine, University of Washington, Seattle, Washington, USA
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA
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17
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Wheeler AM, Riley TR, Merriman TR. Genetic Risk Scores for the Clinical Rheumatologist. J Clin Rheumatol 2025; 31:26-32. [PMID: 39454094 PMCID: PMC11888151 DOI: 10.1097/rhu.0000000000002152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2024]
Abstract
BACKGROUND/HISTORICAL PERSPECTIVE The advent of genome-wide sequencing and large-scale genetic epidemiological studies has led to numerous opportunities for the application of genetics in clinical medicine. Leveraging this information toward the formation of clinically useful tools has been an ongoing research goal in this area. A genetic risk score (GRS) is a measure that attempts to estimate the cumulative contribution of established genetic risk factors toward an outcome of interest, taking into account the cumulative risk that each of these individual genetic risk factors conveys. The purpose of this perspective is to provide a systematic framework to evaluate a GRS for clinical application. SUMMARY OF CURRENT LITERATURE Since the initial polygenic risk score methodology in 2007, there has been increasing GRS application across the medical literature. In rheumatology, this has included application to rheumatoid arthritis, gout, spondyloarthritis, lupus, and inflammatory arthritis. MAJOR CONCLUSIONS GRSs are particularly relevant to rheumatology, where common diseases have many complex genetic factors contributing to risk. Despite this, there is no widely accepted method for the critical application of a GRS, which can be a particular challenge for the clinical rheumatologist seeking to clinically apply GRSs. This review provides a framework by which the clinician may systematically evaluate a GRS. FUTURE RESEARCH DIRECTIONS As genotyping becomes more accessible and cost-effective, it will become increasingly important to recognize the clinical applicability of GRSs and identify those of the highest utility for patient care. This framework for the evaluation of a GRS will also help ensure reliability among GRS research in rheumatology, thereby helping to advance the field.
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Affiliation(s)
- Austin M. Wheeler
- University of Nebraska Medical Center & VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Thomas R. Riley
- University of Pennsylvania & Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
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Emelyanova MA, Ikonnikova AY. Utilization of molecular genetic approaches for colorectal cancer screening. World J Gastroenterol 2024; 30:4950-4957. [PMID: 39679308 PMCID: PMC11612711 DOI: 10.3748/wjg.v30.i46.4950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/14/2024] [Accepted: 11/01/2024] [Indexed: 11/21/2024] Open
Abstract
The feasibility of population screening for colorectal cancer has been demonstrated in several studies. Most of these studies have considered individual characteristics, diagnostic approaches, epidemiological data, and socioeconomic factors. In this article, we comment on an editorial by Metaxas et al published in the recent issue of the journal. The authors emphasized the need to raise public awareness through health education programs and the possibility of using easily accessible non-invasive screening methods. Here, we focus on non-invasive molecular genetic approaches that can aid in colorectal cancer screening. On the one hand, we highlighted the use of tumor DNA/RNA markers directly for screening and, on the other hand, underline the use of polygenic risk assessment and hereditary predisposition to select individuals for more thorough cancer screening.
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Affiliation(s)
- Marina A Emelyanova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Anna Y Ikonnikova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
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19
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Li S, Dite GS, MacInnis RJ, Bui M, Nguyen TL, Esser VFC, Ye Z, Dowty JG, Makalic E, Sung J, Giles GG, Southey MC, Hopper JL. Causation and familial confounding as explanations for the associations of polygenic risk scores with breast cancer: Evidence from innovative ICE FALCON and ICE CRISTAL analyses. Genet Epidemiol 2024; 48:401-413. [PMID: 38472646 PMCID: PMC11588973 DOI: 10.1002/gepi.22556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 02/23/2024] [Indexed: 03/14/2024]
Abstract
A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL]). Inference is made from the changes in regression coefficients of relatives' PRSs or PRS and family history before and after adjusting for each other. We applied these approaches to two breast cancer PRSs and multiple studies and found that (a) for breast cancer diagnosed at a young age, for example, <50 years, there was no evidence that the PRSs were causal, while (b) for breast cancer diagnosed at later ages, there was consistent evidence for causation explaining increasing amounts of the PRS-disease association. The genetic variants in the PRS might be in linkage disequilibrium with truly causal variants and not causal themselves. These PRSs cause minimal heritability of breast cancer at younger ages. There is also evidence for nongenetic factors shared by first-degree relatives that explain breast cancer familial aggregation. Familial associations are not necessarily due to genes, and genetic associations are not necessarily causal.
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Affiliation(s)
- Shuai Li
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
- Murdoch Children's Research InstituteRoyal Children's HospitalParkvilleVictoriaAustralia
| | - Gillian S. Dite
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Genetic Technologies Ltd.FitzroyVictoriaAustralia
| | - Robert J. MacInnis
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
| | - Minh Bui
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Tuong L. Nguyen
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Vivienne F. C. Esser
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Zhoufeng Ye
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - James G. Dowty
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Enes Makalic
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Joohon Sung
- Division of Genome and Health Big Data, Department of Public Health Sciences, Graduate School of Public HealthSeoul National UniversitySeoulKorea
- Genomic Medicine InstituteSeoul National UniversityEuigwahakgwan #402, Seoul National University College of Medicine, 103, Daehak‐ro, Jongno‐guSeoulSouth Korea
- Institute of Health and EnvironmentSeoul National University1st GwanakRoSeoulSouth Korea
| | - Graham G. Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
| | - Melissa C. Southey
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
- Department of Clinical PathologyThe University of MelbourneParkvilleVictoriaAustralia
| | - John L. Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
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Fu R, Chen X, Niedermaier T, Seum T, Hoffmeister M, Brenner H. Nine-fold variation of risk of advanced colorectal neoplasms according to smoking and polygenic risk score: Results from a cross-sectional study in a large screening colonoscopy cohort. Cancer Commun (Lond) 2024; 44:1414-1417. [PMID: 39417395 DOI: 10.1002/cac2.12618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 09/13/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Affiliation(s)
- Ruojin Fu
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- College of Pharmacy, Jinan University, Guangdong, P. R. China
| | - Tobias Niedermaier
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Teresa Seum
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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21
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Hopper JL, Li S, MacInnis RJ, Dowty JG, Nguyen TL, Bui M, Dite GS, Esser VFC, Ye Z, Makalic E, Schmidt DF, Goudey B, Alpen K, Kapuscinski M, Win AK, Dugué P, Milne RL, Jayasekara H, Brooks JD, Malta S, Calais‐Ferreira L, Campbell AC, Young JT, Nguyen‐Dumont T, Sung J, Giles GG, Buchanan D, Winship I, Terry MB, Southey MC, Jenkins MA. Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies. Genet Epidemiol 2024; 48:433-447. [PMID: 38504141 PMCID: PMC11589006 DOI: 10.1002/gepi.22555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 01/29/2024] [Accepted: 02/23/2024] [Indexed: 03/21/2024]
Abstract
Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.
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Affiliation(s)
- John L. Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Shuai Li
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
- Murdoch Children's Research InstituteRoyal Children's HospitalParkvilleVictoriaAustralia
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
| | - Robert J. MacInnis
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
| | - James G. Dowty
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Tuong L. Nguyen
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Minh Bui
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Gillian S. Dite
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Genetic Technologies Ltd.FitzroyVictoriaAustralia
| | - Vivienne F. C. Esser
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Zhoufeng Ye
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Enes Makalic
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Daniel F. Schmidt
- Department of Data Science and AI, Faculty of Information TechnologyMonash UniversityMelbourneVictoriaAustralia
| | - Benjamin Goudey
- ARC Training Centre in Cognitive Computing for Medical TechnologiesUniversity of MelbourneCarltonVictoriaAustralia
- The Florey Department of Neuroscience and Mental HealthThe University of MelbourneParkvilleVictoriaAustralia
| | - Karen Alpen
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Miroslaw Kapuscinski
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- University of Melbourne Centre for Cancer ResearchVictorian Comprehensive Cancer CentreMelbourneVictoriaAustralia
- Genetic MedicineRoyal Melbourne HospitalParkvilleVictoriaAustralia
| | - Pierre‐Antoine Dugué
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
| | - Roger L. Milne
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
| | - Harindra Jayasekara
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
| | - Jennifer D. Brooks
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
| | - Sue Malta
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Lucas Calais‐Ferreira
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
| | - Alexander C. Campbell
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Murdoch Children's Research InstituteRoyal Children's HospitalParkvilleVictoriaAustralia
| | - Jesse T. Young
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
- Institute for Mental Health Policy ResearchCentre for Addiction and Mental HealthTorontoOntarioCanada
- Centre for Adolescent HealthMurdoch Children's Research InstituteParkvilleVictoriaAustralia
- School of Population and Global HealthThe University of Western AustraliaPerthWestern AustraliaAustralia
- Justice Health Group, Curtin School of Population HealthCurtin UniversityPerthWestern AustraliaAustralia
| | - Tu Nguyen‐Dumont
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
| | - Joohon Sung
- Department of Public Health Sciences, Division of Genome and Health Big Data, Graduate School of Public HealthSeoul National UniversitySeoulSouth Korea
- Genome Medicine InstituteSeoul National UniversitySeoulSouth Korea
- Institute of Health and EnvironmentSeoul National UniversitySeoulSouth Korea
| | - Graham G. Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
| | - Daniel Buchanan
- Department of Clinical PathologyThe University of MelbourneParkvilleVictoriaAustralia
| | - Ingrid Winship
- Department of Medicine, Royal Melbourne HospitalThe University of MelbourneParkvilleVictoriaAustralia
| | - Mary Beth Terry
- Department of Epidemiology, Mailman School of Public HealthColumbia UniversityNew YorkNew YorkUSA
| | - Melissa C. Southey
- Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia
- Department of Clinical PathologyThe University of MelbourneParkvilleVictoriaAustralia
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneCarltonVictoriaAustralia
- University of Melbourne Centre for Cancer ResearchVictorian Comprehensive Cancer CentreMelbourneVictoriaAustralia
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22
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Gao N, Zhuang Y, Zheng Y, Li Y, Wang Y, Zhu S, Fan M, Tian W, Jiang Y, Wang Y, Cui M, Suo C, Zhang T, Jin L, Chen X, Xu K. Investigating the link between gut microbiome and bone mineral density: The role of genetic factors. Bone 2024; 188:117239. [PMID: 39179139 DOI: 10.1016/j.bone.2024.117239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/19/2024] [Accepted: 08/17/2024] [Indexed: 08/26/2024]
Abstract
Osteoporosis is a complex metabolic bone disease that severely undermines the quality of life and overall health of the elderly. While previous studies have established a close relationship between gut microbiome and host bone metabolism, the role of genetic factors has received less scrutiny. This research aims to identify potential taxa associated with various bone mineral density states, incorporating assessments of genetic factors. Fecal microbiome profiles from 605 individuals (334 females and 271 males) aged 55-65 from the Taizhou Imaging Study with osteopenia (n = 270, 170 women) or osteoporosis (n = 94, 85 women) or normal (n = 241, 79 women) were determined using shotgun metagenomic sequencing. The linear discriminant analysis was employed to identify differentially enriched taxa. Utilizing the Kyoto Encyclopedia of Genes and Genomes for annotation, functional pathway analysis was conducted to identify differentially metabolic pathways. Polygenic risk score for osteoporosis was estimated to represent genetic susceptibility to osteoporosis, followed by stratification and interaction analyses. Gut flora diversity did not show significant differences among various bone mineral groups. After multivariable adjustment, certain species, such as Clostridium leptum, Fusicatenibacter saccharivorans and Roseburia hominis, were enriched in osteoporosis patients. Statistically significant interactions between the polygenic risk score and taxa Roseburia faecis, Megasphaera elsdenii were observed (P for interaction = 0.005, 0.018, respectively). Stratified analyses revealed a significantly negative association between Roseburia faecis and bone mineral density in the low-genetic-risk group (β = -0.045, P < 0.05), while Turicimonas muris was positively associated with bone mineral density in the high-genetic-risk group (β = 4.177, P < 0.05) after multivariable adjustments. Functional predictions of the gut microbiome indicated an increase in pathways related to structural proteins in high-genetic-risk patients, while low-genetic-risk patients exhibited enrichment in enzyme-related pathways. This study emphasizes the association between gut microbes and bone mass, offering new insights into the interaction between genetic background and gut microbiome.
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Affiliation(s)
- Ningxin Gao
- Department of Biostatistics, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Yue Zhuang
- Department of Biostatistics, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Yi Zheng
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Yucan Li
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Yawen Wang
- Department of Biostatistics, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Sibo Zhu
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Min Fan
- Taixing Disease Control and Prevention Center, Taizhou, Jiangsu, China
| | - Weizhong Tian
- Taizhou People's Hospital Affiliated to Nantong University, Taizhou, Jiangsu, China
| | - Yanfeng Jiang
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Yingzhe Wang
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Mei Cui
- Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China; Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chen Suo
- Department of Biostatistics, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Tiejun Zhang
- Department of Biostatistics, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China.
| | - Kelin Xu
- Department of Biostatistics, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China.
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23
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Mallabar-Rimmer B, Merriel SWD, Webster AP, Jackson L, Wood AR, Barclay M, Tyrrell J, Ruth KS, Thirlwell C, Oram R, Weedon MN, Bailey SER, Green HD. Colorectal cancer risk stratification using a polygenic risk score in symptomatic primary care patients-a UK Biobank retrospective cohort study. Eur J Hum Genet 2024; 32:1456-1464. [PMID: 39090236 DOI: 10.1038/s41431-024-01654-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 05/15/2024] [Accepted: 06/17/2024] [Indexed: 08/04/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Accurate cancer risk assessment approaches could increase rates of early CRC diagnosis, improve health outcomes for patients and reduce pressure on diagnostic services. The faecal immunochemical test (FIT) for blood in stool is widely used in primary care to identify symptomatic patients with likely CRC. However, there is a 6-16% noncompliance rate with FIT in clinic and ~90% of patients over the symptomatic 10 µg/g test threshold do not have CRC. A polygenic risk score (PRS) quantifies an individual's genetic risk of a condition based on many common variants. Existing PRS for CRC have so far been used to stratify asymptomatic populations. We conducted a retrospective cohort study of 50,387 UK Biobank participants with a CRC symptom in their primary care record at age 40+. A PRS based on 201 variants, 5 genetic principal components and 22 other risk factors and markers for CRC were assessed for association with CRC diagnosis within 2 years of first symptom presentation using logistic regression. Associated variables were included in an integrated risk model and trained in 80% of the cohort to predict CRC diagnosis within 2 years. An integrated risk model combining PRS, age, sex, and patient-reported symptoms was predictive of CRC development in a testing cohort (receiver operating characteristic area under the curve, ROCAUC: 0.76, 95% confidence interval: 0.71-0.81). This model has the potential to improve early diagnosis of CRC, particularly in cases of patient noncompliance with FIT.
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Affiliation(s)
| | - Samuel W D Merriel
- Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK
| | - Amy P Webster
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Leigh Jackson
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Andrew R Wood
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Matthew Barclay
- Department of Behavioural Science & Health, Institute of Epidemiology & Health Care, University College London, London, UK
| | - Jessica Tyrrell
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Katherine S Ruth
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | | | - Richard Oram
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Michael N Weedon
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Sarah E R Bailey
- Department of Health and Community Sciences, University of Exeter, Exeter, UK
| | - Harry D Green
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
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24
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Byrjalsen A, Garcia SL, Borgwardt L, Wadt K, Gerdes AM, van Overeem Hansen T. Rare germline chromosome 1 duplication identified in young male with colon cancer: a case report investigating causality. J Gastrointest Oncol 2024; 15:2316-2322. [PMID: 39554577 PMCID: PMC11565109 DOI: 10.21037/jgo-24-148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/27/2024] [Indexed: 11/19/2024] Open
Abstract
Background The occurrence of colorectal cancer (CRC) is increasing among young adults, but the etiology is still largely unknown. In addition to germline monogenetic variants also polygenic risk scores (PRS) have been proven to correctly estimate the risk of CRC. Case Description We present a 24-year-old male with disseminated colon cancer who carried a germline duplication on chromosome 1 spanning 200 kb and covering CD101, TTF2, MIR942, TRIM45, and parts of PTGFRN and VTCN1. The duplication was located in tandem. A similar duplication was previously reported in a family with CRC among two brothers aged 52 and 61 years old at diagnosis. Particularly, MIR942 was an interesting finding as it is involved in the regulation of the Wnt signaling pathway. Disruption of the Wnt pathway is known to cause CRC. However, in our case the duplication did not segregate with disease in the family. Calculation of a PRS in our patient found an average PRS for CRC. Conclusions Our findings do not support that this duplication is a monogenetic cause of CRC, nor did a PRS point towards an increased risk in this 24-year-old male. Whether the duplication is a risk factor in combination with other genetic and non-genetic risk factors requires further studies.
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Affiliation(s)
- Anna Byrjalsen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sara L. Garcia
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Line Borgwardt
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Karin Wadt
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne Marie Gerdes
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas van Overeem Hansen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Nakase T, Guerra GA, Ostrom QT, Ge T, Melin BS, Wrensch M, Wiencke JK, Jenkins RB, Eckel-Passow JE, Glioma International Case-Control Study (GICC), Bondy ML, Francis SS, Kachuri L. Genome-wide polygenic risk scores predict risk of glioma and molecular subtypes. Neuro Oncol 2024; 26:1933-1944. [PMID: 38916140 PMCID: PMC11448969 DOI: 10.1093/neuonc/noae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to efficiently capture genetic risk using available data. METHODS We applied a method based on continuous shrinkage priors (PRS-CS) to model the joint effects of over 1 million common variants on disease risk and compared this to an approach (PRS-CT) that only selects a limited set of independent variants that reach genome-wide significance (P < 5 × 10-8). PRS models were trained using GWAS stratified by histological (10 346 cases and 14 687 controls) and molecular subtype (2632 cases and 2445 controls), and validated in 2 independent cohorts. RESULTS PRS-CS was generally more predictive than PRS-CT with a median increase in explained variance (R2) of 24% (interquartile range = 11-30%) across glioma subtypes. Improvements were pronounced for glioblastoma (GBM), with PRS-CS yielding larger odds ratios (OR) per standard deviation (SD) (OR = 1.93, P = 2.0 × 10-54 vs. OR = 1.83, P = 9.4 × 10-50) and higher explained variance (R2 = 2.82% vs. R2 = 2.56%). Individuals in the 80th percentile of the PRS-CS distribution had a significantly higher risk of GBM (0.107%) at age 60 compared to those with average PRS (0.046%, P = 2.4 × 10-12). Lifetime absolute risk reached 1.18% for glioma and 0.76% for IDH wildtype tumors for individuals in the 95th PRS percentile. PRS-CS augmented the classification of IDH mutation status in cases when added to demographic factors (AUC = 0.839 vs. AUC = 0.895, PΔAUC = 6.8 × 10-9). CONCLUSIONS Genome-wide PRS has the potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.
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Affiliation(s)
- Taishi Nakase
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA
| | - Geno A Guerra
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
| | - Quinn T Ostrom
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Tian Ge
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Psychiatry, Center for Precision Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Beatrice S Melin
- Department of Diagnostics and Intervention, Oncology Umeå University, Umeå, Sweden
| | - Margaret Wrensch
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
| | - John K Wiencke
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
| | - Robert B Jenkins
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Melissa L Bondy
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
| | - Stephen S Francis
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
- Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
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Lee PH, Chen IC, Chen YM, Hsiao TH, Tseng JS, Huang YH, Hsu KH, Lin H, Yang TY, Shao YHJ. Using a Polygenic Risk Score to Improve the Risk Prediction of Non-Small Cell Lung Cancer in Taiwan. JCO Precis Oncol 2024; 8:e2400236. [PMID: 39348659 DOI: 10.1200/po.24.00236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/18/2024] [Accepted: 08/20/2024] [Indexed: 10/02/2024] Open
Abstract
PURPOSE Low-dose computed tomography (LDCT) can help reducing lung cancer mortality. In Taiwan, the existing screening criteria revolve around smoking habits and family history of lung cancer. The role of genetic variation in non-small cell lung cancer (NSCLC) development is increasingly recognized. In this study, we aimed to investigate the potential benefits of polygenic risk scores (PRSs) in predicting NSCLC and enhancing the effectiveness of screening programs. METHODS We conducted a retrospective cohort study that included participants without prior diagnosis of lung cancer and later received LDCT for lung cancer screening. Genetic data for these participants were obtained from the project of Taiwan Precision Medicine Initiative. We adopted the model of genome-wide association study-derived PRS calculation using 19 susceptibility loci associated with the risk of NSCLC as reported by Dai et al. RESULTS We studied a total of 2,287 participants (1,197 male, 1,090 female). More female participants developed NSCLC during the follow-up period (4.4% v 2.5%, P = .015). The only risk factor of NSCLC diagnosis among male participants was age. Among female participants, independent risk factors of NSCLC diagnosis were age (adjusted hazard ratio [aHR], 1.08 [95% CI, 1.04 to 1.11]), a family history of lung cancer (aHR, 3.21 [95% CI, 1.78 to 5.77]), and PRS fourth quartile (aHR, 2.97 [95% CI, 1.25 to 7.07]). We used the receiver operating characteristics to show an AUC value of 0.741 for the conventional model. With the further incorporation of PRS, the AUC rose to 0.778. CONCLUSION The evaluation of PRS for NSCLC prediction holds promise for enhancing the effectiveness of lung cancer screening in Taiwan especially in women. By incorporating genetic information, screening criteria can be tailored to identify individuals at higher risks of NSCLC.
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Affiliation(s)
- Po-Hsin Lee
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Rong Hsing Translational Medicine Research Center, National Chung Hsing University, Taichung, Taiwan
| | - I-Chieh Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yi-Ming Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Rong Hsing Translational Medicine Research Center, National Chung Hsing University, Taichung, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Tzu-Hung Hsiao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan
| | - Jeng-Sen Tseng
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yen-Hsiang Huang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Kuo-Hsuan Hsu
- Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ho Lin
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Tsung-Ying Yang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yu-Hsuan Joni Shao
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei, Taiwan
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Mauri G, Patelli G, Sartore-Bianchi A, Abrignani S, Bodega B, Marsoni S, Costanzo V, Bachi A, Siena S, Bardelli A. Early-onset cancers: Biological bases and clinical implications. Cell Rep Med 2024; 5:101737. [PMID: 39260369 PMCID: PMC11525030 DOI: 10.1016/j.xcrm.2024.101737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/02/2024] [Accepted: 08/19/2024] [Indexed: 09/13/2024]
Abstract
Since the nineties, the incidence of sporadic early-onset (EO) cancers has been rising worldwide. The underlying reasons are still unknown. However, identifying them is vital for advancing both prevention and intervention. Here, we exploit available knowledge derived from clinical observations to formulate testable hypotheses aimed at defining the causal factors of this epidemic and discuss how to experimentally test them. We explore the potential impact of exposome changes from the millennials to contemporary young generations, considering both environmental exposures and enhanced susceptibilities to EO-cancer development. We emphasize how establishing the time required for an EO cancer to develop is relevant to defining future screening strategies. Finally, we discuss the importance of integrating multi-dimensional data from international collaborations to generate comprehensive knowledge and translate these findings back into clinical practice.
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Affiliation(s)
- Gianluca Mauri
- IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giorgio Patelli
- IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Andrea Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Sergio Abrignani
- INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Beatrice Bodega
- INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy
| | - Silvia Marsoni
- IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy
| | - Vincenzo Costanzo
- IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Angela Bachi
- IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy
| | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Alberto Bardelli
- IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy.
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Lei Y, Christian Naj A, Xu H, Li R, Chen Y. Balancing the efforts of chart review and gains in PRS prediction accuracy: An empirical study. J Biomed Inform 2024; 157:104705. [PMID: 39134233 DOI: 10.1016/j.jbi.2024.104705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/12/2024] [Accepted: 08/05/2024] [Indexed: 08/22/2024]
Abstract
OBJECTIVE Phenotypic misclassification in genetic association analyses can impact the accuracy of PRS-based prediction models. The bias reduction method proposed by Tong et al. (2019) has demonstrated its efficacy in reducing the effects of bias on the estimation of association parameters between genotype and phenotype while minimizing variance by employing chart reviews on a subset of the data for validating phenotypes, however its improvement of subsequent PRS prediction accuracy remains unclear. Our study aims to fill this gap by assessing the performance of simulated PRS models and estimating the optimal number of chart reviews needed for validation. METHODS To comprehensively assess the efficacy of the bias reduction method proposed by Tong et al. in enhancing the accuracy of PRS-based prediction models, we simulated each phenotype under different correlation structures (an independent model, a weakly correlated model, a strongly correlated model) and introduced error-prone phenotypes using two distinct error mechanisms (differential and non-differential phenotyping errors). To facilitate this, we used genotype and phenotype data from 12 case-control datasets in the Alzheimer's Disease Genetics Consortium (ADGC) to produce simulated phenotypes. The evaluation included analyses across various misclassification rates of original phenotypes as well as quantities of validation set. Additionally, we determined the median threshold, identifying the minimal validation size required for a meaningful improvement in the accuracy of PRS-based predictions across a broad spectrum. RESULTS This simulation study demonstrated that incorporating chart review does not universally guarantee enhanced performance of PRS-based prediction models. Specifically, in scenarios with minimal misclassification rates and limited validation sizes, PRS models utilizing debiased regression coefficients demonstrated inferior predictive capabilities compared to models using error-prone phenotypes. Put differently, the effectiveness of the bias reduction method is contingent upon the misclassification rates of phenotypes and the size of the validation set employed during chart reviews. Notably, when dealing with datasets featuring higher misclassification rates, the advantages of utilizing this bias reduction method become more evident, requiring a smaller validation set to achieve better performance. CONCLUSION This study highlights the importance of choosing an appropriate validation set size to balance between the efforts of chart review and the gain in PRS prediction accuracy. Consequently, our study establishes a valuable guidance for validation planning, across a diverse array of sensitivity and specificity combinations.
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Affiliation(s)
- Yuqing Lei
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - Adam Christian Naj
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA; Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - Hua Xu
- Department for Biomedical Informatics and Data Science, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Ruowang Li
- Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Yong Chen
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
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Sun C, Cheng X, Xu J, Chen H, Tao J, Dong Y, Wei S, Chen R, Meng X, Ma Y, Tian H, Guo X, Bi S, Zhang C, Kang J, Zhang M, Lv H, Shang Z, Lv W, Zhang R, Jiang Y. A review of disease risk prediction methods and applications in the omics era. Proteomics 2024; 24:e2300359. [PMID: 38522029 DOI: 10.1002/pmic.202300359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 03/08/2024] [Accepted: 03/12/2024] [Indexed: 03/25/2024]
Abstract
Risk prediction and disease prevention are the innovative care challenges of the 21st century. Apart from freeing the individual from the pain of disease, it will lead to low medical costs for society. Until very recently, risk assessments have ushered in a new era with the emergence of omics technologies, including genomics, transcriptomics, epigenomics, proteomics, and so on, which potentially advance the ability of biomarkers to aid prediction models. While risk prediction has achieved great success, there are still some challenges and limitations. We reviewed the general process of omics-based disease risk model construction and the applications in four typical diseases. Meanwhile, we highlighted the problems in current studies and explored the potential opportunities and challenges for future clinical practice.
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Affiliation(s)
- Chen Sun
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
| | - Xiangshu Cheng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
| | - Jing Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
| | - Haiyan Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Junxian Tao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
| | - Yu Dong
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
| | - Siyu Wei
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
| | - Rui Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xin Meng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yingnan Ma
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
| | - Hongsheng Tian
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xuying Guo
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Shuo Bi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Chen Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jingxuan Kang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Mingming Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hongchao Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Zhenwei Shang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Wenhua Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Ruijie Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yongshuai Jiang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- The EWAS Project, Harbin, China
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Fu R, Chen X, Niedermaier T, Seum T, Hoffmeister M, Brenner H. Excess Weight, Polygenic Risk Score, and Findings of Colorectal Neoplasms at Screening Colonoscopy. Am J Gastroenterol 2024; 119:1913-1920. [PMID: 38704818 PMCID: PMC11365593 DOI: 10.14309/ajg.0000000000002853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 04/25/2024] [Indexed: 05/07/2024]
Abstract
INTRODUCTION Excess weight is an established risk factor of colorectal cancer (CRC). However, evidence is lacking on how its impact varies by polygenic risk at different stages of colorectal carcinogenesis. METHODS We assessed the individual and joint associations of body mass index (BMI) and polygenic risk scores (PRSs) with findings of colorectal neoplasms among 4,784 participants of screening colonoscopy. Adjusted odds ratios (aORs) for excess weight derived by multiple logistic regression were converted to genetic risk equivalents (GREs) to quantify the impact of excess weight compared with genetic predisposition. RESULTS Overweight and obesity (BMI 25-<30 and ≥30 kg/m 2 ) were associated with increased risk of any colorectal neoplasm (aOR [95% confidence interval, CI] 1.26 [1.09-1.45] and 1.47 [1.24-1.75]). Obesity was associated with increased risk of advanced colorectal neoplasm (aOR [95% CI] 1.46 [1.16-1.84]). Dose-response relationships were seen for the PRS (stronger for advanced neoplasms than any neoplasms), with no interaction with BMI, suggesting multiplicative effects of both factors. Obese participants with a PRS in the highest tertile had a 2.3-fold (95% CI 1.7-3.1) and 2.9-fold (95% CI 1.9-4.3) increased risk of any colorectal neoplasm and advanced colorectal neoplasm, respectively. The aOR of obesity translated into a GRE of 38, meaning that its impact was estimated to be equivalent to the risk caused by 38 percentiles higher PRS for colorectal neoplasm. DISCUSSION Excess weight and polygenic risk are associated with increased risk of colorectal neoplasms in a multiplicative manner. Maintaining normal weight is estimated to have an equivalent effect as having 38 percentiles lower PRS.
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Affiliation(s)
- Ruojin Fu
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Tobias Niedermaier
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Teresa Seum
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
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Fu R, Chen X, Seum T, Hoffmeister M, Brenner H. Red and Processed Meat Intake, Polygenic Risk and the Prevalence of Colorectal Neoplasms: Results from a Screening Colonoscopy Population. Nutrients 2024; 16:2609. [PMID: 39203746 PMCID: PMC11357662 DOI: 10.3390/nu16162609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/03/2024] Open
Abstract
High red and processed meat intake and genetic predisposition are risk factors of colorectal cancer (CRC). However, evidence of their independent and joint associations on the risk of colorectal neoplasms is limited. We assessed these associations among 4774 men and women undergoing screening colonoscopy. Polygenic risk scores (PRSs) were calculated based on 140 loci related to CRC. We used multiple logistic regression models to evaluate the associations of red and processed meat intake and PRS with the risk of colorectal neoplasms. Adjusted odds ratios (aORs) were translated to genetic risk equivalents (GREs) to compare the strength of the associations with colorectal neoplasm risk of both factors. Compared to ≤1 time/week, processed meat intake >1 time/week was associated with a significantly increased risk of colorectal neoplasm [aOR (95% CI): 1.28 (1.12-1.46)]. This risk increase was equivalent to the risk increase associated with a 19 percentile higher PRS. The association of red meat intake with colorectal neoplasm was weaker and did not reach statistical significance. High processed meat intake and PRS contribute to colorectal neoplasm risk independently. Limiting processed meat intake may offset a substantial proportion of the genetically increased risk of colorectal neoplasms.
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Affiliation(s)
- Ruojin Fu
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany
| | - Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
- College of Pharmacy, Jinan University, Guangzhou 511436, China
| | - Teresa Seum
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Dezfuli AAZ, Abu-Elghait M, Salem SS. Recent Insights into Nanotechnology in Colorectal Cancer. Appl Biochem Biotechnol 2024; 196:4457-4471. [PMID: 37751009 DOI: 10.1007/s12010-023-04696-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2023] [Indexed: 09/27/2023]
Abstract
Colorectal cancer (CRC) is the third cancer among the known causes of cancer that impact people. Although CRC drug options are imperfect, primary detection of CRC can play a key role in treating the disease and reducing mortality. Cancer tissues show many molecular markers that can be used as a new way to advance therapeutic methods. Nanotechnology includes a wide range of nanomaterials with high diagnostic and therapeutic power. Several nanomaterials and nanoformulations can be used to treat cancer, especially CRC. In this review, we discuss recent insights into nanotechnology in colorectal cancer.
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Affiliation(s)
- Aram Asareh Zadegan Dezfuli
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Mohammed Abu-Elghait
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Salem S Salem
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Cairo, Egypt.
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Ye Y, Xu G. Construction of a new prognostic model for colorectal cancer based on bulk RNA-seq combined with The Cancer Genome Atlas data. Transl Cancer Res 2024; 13:2704-2720. [PMID: 38988915 PMCID: PMC11231782 DOI: 10.21037/tcr-23-2281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 05/08/2024] [Indexed: 07/12/2024]
Abstract
Background Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths, and improving the prognosis of CRC patients is an urgent concern. The aim of this study was to explore new immunotherapy targets to improve survival in CRC patients. Methods We analyzed CRC-related single-cell data GSE201348 from the Gene Expression Omnibus (GEO) database, and identified differentially expressed genes (DEGs). Subsequently, we performed differential analysis on the rectum adenocarcinoma (READ) and colon adenocarcinoma (COAD) transcriptome sequencing data [The Cancer Genome Atlas (TCGA)-CRC queue] and clinical data downloaded from TCGA database. Subgroup analysis was performed using CIBERSORTx and cluster analysis. Finally, biomarkers were identified by one-way cox regression as well as least absolute shrinkage and selection operator (LASSO) analysis. Results In this study, we analyzed CRC-related single-cell data GSE201348, and identified 5,210 DEGs. Subsequently, we performed differential analysis on the TCGA-CRC queue database, and obtained 4,408 DEGs. Then, we categorized the cancer samples in the sequencing data into three groups (k1, k2, and k3), with significant differences observed between the k1 and k2 groups via survival analysis. Further differential analysis on the samples in the k1 and k2 groups identified 1,899 DEGs. A total of 77 DEGs were selected among those DEGs obtained from three differential analyses. Through subsequent Cox univariate analysis and LASSO analysis, seven biomarkers (RETNLB, CLCA4, UGT2A3, SULT1B1, CCL24, BMP5, and ATOH1) were identified and selected to establish a risk score (RS). Conclusions To sum up, this study demonstrates the potential of the seven-gene prognostic risk model as instrumental variables for predicting the prognosis of CRC.
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Affiliation(s)
- Yu Ye
- Department of General Surgery, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, China
| | - Gang Xu
- Department of General Surgery, Zhejiang Hospital, Hangzhou, China
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Zhang Y, Sheng C, Lyu Z, Dai H, Song F, Song F, Huang Y, Chen K. Effectiveness of colorectal cancer screening integrating non-genetic and genetic risk: a prospective study based on UK Biobank data. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0096. [PMID: 38899940 PMCID: PMC11359493 DOI: 10.20892/j.issn.2095-3941.2024.0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
OBJECTIVE Few studies have evaluated the benefits of colorectal cancer (CRC) screening integrating both non-genetic and genetic risk factors. Here, we aimed to integrate an existing non-genetic risk model (QCancer-10) and a 139-variant polygenic risk score to evaluate the effectiveness of screening on CRC incidence and mortality. METHODS We applied the integrated model to calculate 10-year CRC risk for 430,908 participants in the UK Biobank, and divided the participants into low-, intermediate-, and high-risk groups. We calculated the screening-associated hazard ratios (HRs) and absolute risk reductions (ARRs) for CRC incidence and mortality according to risk stratification. RESULTS During a median follow-up of 11.03 years and 12.60 years, we observed 5,158 CRC cases and 1,487 CRC deaths, respectively. CRC incidence and mortality were significantly lower among screened than non-screened participants in both the intermediate- and high-risk groups [incidence: HR: 0.87, 95% confidence interval (CI): 0.81-0.94; 0.81, 0.73-0.90; mortality: 0.75, 0.64-0.87; 0.70, 0.58-0.85], which composed approximately 60% of the study population. The ARRs (95% CI) were 0.17 (0.11-0.24) and 0.43 (0.24-0.61), respectively, for CRC incidence, and 0.08 (0.05-0.11) and 0.24 (0.15-0.33), respectively, for mortality. Screening did not significantly reduce the relative or absolute risk of CRC incidence and mortality in the low-risk group. Further analysis revealed that screening was most effective for men and individuals with distal CRC among the intermediate to high-risk groups. CONCLUSIONS After integrating both genetic and non-genetic factors, our findings provided priority evidence of risk-stratified CRC screening and valuable insights for the rational allocation of health resources.
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Affiliation(s)
- Yu Zhang
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Chao Sheng
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Zhangyan Lyu
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Hongji Dai
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Fangfang Song
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Fengju Song
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Yubei Huang
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
| | - Kexin Chen
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Human Major Diseases, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
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Fu QQ, Ma L, Niu XM, Zhao HX, Ge XH, Jin H, Yu DH, Yang S. Trends and hotspots in gastrointestinal neoplasms risk assessment: A bibliometric analysis from 1984 to 2022. World J Gastrointest Oncol 2024; 16:2842-2861. [PMID: 38994129 PMCID: PMC11236220 DOI: 10.4251/wjgo.v16.i6.2842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 03/10/2024] [Accepted: 04/15/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Gastrointestinal neoplasm (GN) significantly impact the global cancer burden and mortality, necessitating early detection and treatment. Understanding the evolution and current state of research in this field is vital. AIM To conducts a comprehensive bibliometric analysis of publications from 1984 to 2022 to elucidate the trends and hotspots in the GN risk assessment research, focusing on key contributors, institutions, and thematic evolution. METHODS This study conducted a bibliometric analysis of data from the Web of Science Core Collection database using the "bibliometrix" R package, VOSviewer, and CiteSpace. The analysis focused on the distribution of publications, contributions by institutions and countries, and trends in keywords. The methods included data synthesis, network analysis, and visualization of international collaboration networks. RESULTS This analysis of 1371 articles on GN risk assessment revealed a notable evolution in terms of research focus and collaboration. It highlights the United States' critical role in advancing this field, with significant contributions from institutions such as Brigham and Women's Hospital and the National Cancer Institute. The last five years, substantial advancements have been made, representing nearly 45% of the examined literature. Publication rates have dramatically increased, from 20 articles in 2002 to 112 in 2022, reflecting intensified research efforts. This study underscores a growing trend toward interdisciplinary and international collaboration, with the Journal of Clinical Oncology standing out as a key publication outlet. This shift toward more comprehensive and collaborative research methods marks a significant step in addressing GN risks. CONCLUSION This study underscores advancements in GN risk assessment through genetic analyses and machine learning and reveals significant geographical disparities in research emphasis. This calls for enhanced global collaboration and integration of artificial intelligence to improve cancer prevention and treatment accuracy, ultimately enhancing worldwide patient care.
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Affiliation(s)
- Qiang-Qiang Fu
- Department of General Practice, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
- Shanghai General Practice and Community Health Development Research Center, Shanghai 200090, China
| | - Le Ma
- Department of General Practice, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
| | - Xiao-Min Niu
- Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Hua-Xin Zhao
- Department of Oncology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xu-Hua Ge
- Department of General Practice, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
| | - Hua Jin
- Department of General Practice, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
| | - De-Hua Yu
- Department of General Practice, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
- Shanghai General Practice and Community Health Development Research Center, Shanghai 200090, China
| | - Sen Yang
- Department of General Practice, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
- Shanghai General Practice and Community Health Development Research Center, Shanghai 200090, China
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Tian J, Zhang M, Zhang F, Gao K, Lu Z, Cai Y, Chen C, Ning C, Li Y, Qian S, Bai H, Liu Y, Zhang H, Chen S, Li X, Wei Y, Li B, Zhu Y, Yang J, Jin M, Miao X, Chen K. Developing an optimal stratification model for colorectal cancer screening and reducing racial disparities in multi-center population-based studies. Genome Med 2024; 16:81. [PMID: 38872215 PMCID: PMC11170922 DOI: 10.1186/s13073-024-01355-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 06/05/2024] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. METHODS To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. RESULTS Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose-response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). CONCLUSIONS Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.
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Affiliation(s)
- Jianbo Tian
- Department of Epidemiology and Biostatistics, School of Public Health, Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
- Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
| | - Ming Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
- Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Fuwei Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
- Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Kai Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
- Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zequn Lu
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Yimin Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Can Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Caibo Ning
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Yanmin Li
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Sangni Qian
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
- Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Bai
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
- Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yizhuo Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Heng Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Shuoni Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Xiangpan Li
- Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Yongchang Wei
- Department of Gastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bin Li
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Ying Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
| | - Jinhua Yang
- Jiashan Institute of Cancer Prevention and Treatment, Jiashan, China
| | - Mingjuan Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
- Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Xiaoping Miao
- Department of Epidemiology and Biostatistics, School of Public Health, Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
- Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
- Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
| | - Kun Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
- Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Grunin M, Triffon D, Beykin G, Rahmani E, Schweiger R, Tiosano L, Khateb S, Hagbi-Levi S, Rinsky B, Munitz R, Winkler TW, Heid IM, Halperin E, Carmi S, Chowers I. Genome wide association study and genomic risk prediction of age related macular degeneration in Israel. Sci Rep 2024; 14:13034. [PMID: 38844476 PMCID: PMC11156861 DOI: 10.1038/s41598-024-63065-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 05/24/2024] [Indexed: 06/09/2024] Open
Abstract
The risk of developing age-related macular degeneration (AMD) is influenced by genetic background. In 2016, the International AMD Genomics Consortium (IAMDGC) identified 52 risk variants in 34 loci, and a polygenic risk score (PRS) from these variants was associated with AMD. The Israeli population has a unique genetic composition: Ashkenazi Jewish (AJ), Jewish non-Ashkenazi, and Arab sub-populations. We aimed to perform a genome-wide association study (GWAS) for AMD in Israel, and to evaluate PRSs for AMD. Our discovery set recruited 403 AMD patients and 256 controls at Hadassah Medical Center. We genotyped individuals via custom exome chip. We imputed non-typed variants using cosmopolitan and AJ reference panels. We recruited additional 155 cases and 69 controls for validation. To evaluate predictive power of PRSs for AMD, we used IAMDGC summary-statistics excluding our study and developed PRSs via clumping/thresholding or LDpred2. In our discovery set, 31/34 loci reported by IAMDGC were AMD-associated (P < 0.05). Of those, all effects were directionally consistent with IAMDGC and 11 loci had a P-value under Bonferroni-corrected threshold (0.05/34 = 0.0015). At a 5 × 10-5 threshold, we discovered four suggestive associations in FAM189A1, IGDCC4, C7orf50, and CNTNAP4. Only the FAM189A1 variant was AMD-associated in the replication cohort after Bonferroni-correction. A prediction model including LDpred2-based PRS + covariates had an AUC of 0.82 (95% CI 0.79-0.85) and performed better than covariates-only model (P = 5.1 × 10-9). Therefore, previously reported AMD-associated loci were nominally associated with AMD in Israel. A PRS developed based on a large international study is predictive in Israeli populations.
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Affiliation(s)
- Michelle Grunin
- Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, POB 12271, 9112102, Jerusalem, Israel
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel
| | - Daria Triffon
- Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, POB 12271, 9112102, Jerusalem, Israel
| | - Gala Beykin
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel
| | - Elior Rahmani
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Regev Schweiger
- Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel
- Department of Genetics, University of Cambridge, CB21TN, Cambridge, UK
| | - Liran Tiosano
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel
| | - Samer Khateb
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel
| | - Shira Hagbi-Levi
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel
| | - Batya Rinsky
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel
| | - Refael Munitz
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel
| | - Thomas W Winkler
- Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
| | - Iris M Heid
- Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
| | - Eran Halperin
- Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel
- Department of Anesthesiology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Shai Carmi
- Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, POB 12271, 9112102, Jerusalem, Israel.
| | - Itay Chowers
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel.
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Jiang C, Zhou Q, Yi K, Yuan Y, Xie X. Colorectal cancer initiation: Understanding early-stage disease for intervention. Cancer Lett 2024; 589:216831. [PMID: 38574882 DOI: 10.1016/j.canlet.2024.216831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/06/2024]
Abstract
How tumors arise or the cause of precancerous lesions is a fundamental question in cancer biology. It is generally accepted that tumors originate from normal cells that undergo uncontrolled proliferation owing to genetic alterations. At the onset of adenoma formation, cancer driver mutations confer clonal growth advantage, enabling mutant cells to outcompete and eliminate the surrounding healthy cells. Hence, the development of precancerous lesions is not only attributed to the expansion of pre-malignant clones, but also relies on the relative fitness of mutated cells compared to the neighboring cells. Colorectal cancer (CRC) is an excellent model to investigate cancer origin as it follows a stereotypical process from mutant cell hyperplasia to adenoma formation and progression. Here, we review the evolving understanding of colonic tumor development, focusing on how cell intrinsic and extrinsic factors impact cell competition and the "clone war" between cancer-initiating cells and normal stem cells. We also discuss the promises and limitations of targeting cell competitiveness in cancer prevention and early intervention. The field of tumor initiation is currently in its infancy, elucidating the adenoma origin is crucial for designing effective prevention strategies and early treatments before cancer becomes incurable.
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Affiliation(s)
- Chao Jiang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China
| | - Qiujing Zhou
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China; The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, China
| | - Ke Yi
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Xin Xie
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China; Department of Medical Oncology, Cancer Institute and Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310029, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, 310058, China.
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Hibler EA, Szymaniak B, Abbass MA. Colorectal Cancer Risk between Mendelian and Non-Mendelian Inheritance. Clin Colon Rectal Surg 2024; 37:140-145. [PMID: 38606051 PMCID: PMC11006447 DOI: 10.1055/s-0043-1770382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024]
Abstract
Hereditary colorectal cancer has been an area of focus for research and public health practitioners due to our ability to quantify risk and then act based on such results by enrolling patients in surveillance programs. The wide access to genetic testing and whole-genome sequencing has resulted in identifying many low/moderate penetrance genes. Above all, our understanding of the family component of colorectal cancer has been improving. Polygenic scores are becoming part of the risk assessment for many cancers, and the data about polygenic risk scores for colorectal cancer is promising. The challenge is determining how we incorporate this data in clinical care.
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Affiliation(s)
- Elizabeth A. Hibler
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Brittany Szymaniak
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Mohammad Ali Abbass
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Sullivan BA, Lieberman DA. Colon Polyp Surveillance: Separating the Wheat From the Chaff. Gastroenterology 2024; 166:743-757. [PMID: 38224860 DOI: 10.1053/j.gastro.2023.11.305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 01/17/2024]
Abstract
One goal of colorectal cancer (CRC) screening is to prevent CRC incidence by removing precancerous colonic polyps, which are detected in up to 50% of screening examinations. Yet, the lifetime risk of CRC is 3.9%-4.3%, so it is clear that most of these individuals with polyps would not develop CRC in their lifetime. It is, therefore, a challenge to determine which individuals with polyps will benefit from follow-up, and at what intervals. There is some evidence that individuals with advanced polyps, based on size and histology, benefit from intensive surveillance. However, a large proportion of individuals will have small polyps without advanced histologic features (ie, "nonadvanced"), where the benefits of surveillance are uncertain and controversial. Demand for surveillance will further increase as more polyps are detected due to increased screening uptake, recent United States recommendations to expand screening to younger individuals, and emergence of polyp detection technology. We review the current understanding and clinical implications of the natural history, biology, and outcomes associated with various categories of colon polyps based on size, histology, and number. Our aims are to highlight key knowledge gaps, specifically focusing on certain categories of polyps that may not be associated with future CRC risk, and to provide insights to inform research priorities and potential management strategies. Optimization of CRC prevention programs based on updated knowledge about the future risks associated with various colon polyps is essential to ensure cost-effective screening and surveillance, wise use of resources, and inform efforts to personalize recommendations.
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Affiliation(s)
- Brian A Sullivan
- Cooperative Studies Program Epidemiology Center-Durham, Durham VA Health Care System, Durham, North Carolina; Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
| | - David A Lieberman
- Portland Veteran Affairs Medical Center, Portland, Oregon; Division of Gastroenterology and Hepatology, School of Medicine, Oregon Health and Science University, Portland, Oregon
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Rosenthal EA, Hsu L, Thomas M, Peters U, Kachulis C, Patterson K, Jarvik GP. Comparing ancestry calibration approaches for a trans-ancestry colorectal cancer polygenic risk score. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2023.10.23.23296753. [PMID: 37961088 PMCID: PMC10635167 DOI: 10.1101/2023.10.23.23296753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Background Colorectal cancer (CRC) is a complex disease with monogenic, polygenic and environmental risk factors. Polygenic risk scores (PRS) are being developed to identify high polygenic risk individuals. Due to differences in genetic background, PRS distributions vary by ancestry, necessitating calibration. Methods We compared four calibration methods using the All of Us Research Program Whole Genome Sequence data for a CRC PRS previously developed in participants of European and East Asian ancestry. The methods contrasted results from linear models with A) the entire data set or an ancestrally diverse training set AND B) covariates including principal components of ancestry or admixture. Calibration with the training set adjusted the variance in addition to the mean. Results All methods performed similarly within ancestry with OR (95% C.I.) per s.d. change in PRS: African 1.5 (1.02, 2.08), Admixed American 2.2 (1.27, 3.85), European 1.6 (1.43, 1.89), and Middle Eastern 1.1 (0.71, 1.63). Using admixture and an ancestrally diverse training set provided distributions closest to standard Normal with accurate upper tail frequencies. Conclusion Although the PRS is predictive of CRC risk for most ancestries, its performance varies by ancestry. Post-hoc calibration preserves the risk prediction within ancestries. Training a calibration model on ancestrally diverse participants to adjust both the mean and variance of the PRS, using admixture as covariates, created standard Normal z-scores. These z-scores can be used to identify patients at high polygenic risk, and can be incorporated into comprehensive risk scores including other known risk factors, allowing for more precise risk estimates.
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Tamlander M, Jermy B, Seppälä TT, Färkkilä M, Widén E, Ripatti S, Mars N. Genome-wide polygenic risk scores for colorectal cancer have implications for risk-based screening. Br J Cancer 2024; 130:651-659. [PMID: 38172535 PMCID: PMC10876651 DOI: 10.1038/s41416-023-02536-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Hereditary factors, including single genetic variants and family history, can be used for targeting colorectal cancer (CRC) screening, but limited data exist on the impact of polygenic risk scores (PRS) on risk-based CRC screening. METHODS Using longitudinal health and genomics data on 453,733 Finnish individuals including 8801 CRC cases, we estimated the impact of a genome-wide CRC PRS on CRC screening initiation age through population-calibrated incidence estimation over the life course in men and women. RESULTS Compared to the cumulative incidence of CRC at age 60 in Finland (the current age for starting screening in Finland), a comparable cumulative incidence was reached 5 and 11 years earlier in persons with high PRS (80-99% and >99%, respectively), while those with a low PRS (< 20%) reached comparable incidence 7 years later. The PRS was associated with increased risk of post-colonoscopy CRC after negative colonoscopy (hazard ratio 1.76 per PRS SD, 95% CI 1.54-2.01). Moreover, the PRS predicted colorectal adenoma incidence and improved incident CRC risk prediction over non-genetic risk factors. CONCLUSIONS Our findings demonstrate that a CRC PRS can be used for risk stratification of CRC, with further research needed to optimally integrate the PRS into risk-based screening.
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Affiliation(s)
- Max Tamlander
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Bradley Jermy
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Toni T Seppälä
- Faculty of Medicine and Health Technology, University of Tampere and TAYS Cancer Centre, Tampere, Finland
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
- Applied Tumor Genomics Research Program, University of Helsinki, Helsinki, Finland
- Abdominal Center, Helsinki University Hospital, Helsinki University, Helsinki, Finland
| | - Martti Färkkilä
- Abdominal Center, Helsinki University Hospital, Helsinki University, Helsinki, Finland
| | - Elisabeth Widén
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Samuli Ripatti
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
- Clinicum, Department of Public Health, University of Helsinki, Helsinki, Finland
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nina Mars
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Gibson TM, Karyadi DM, Hartley SW, Arnold MA, Berrington de Gonzalez A, Conces MR, Howell RM, Kapoor V, Leisenring WM, Neglia JP, Sampson JN, Turcotte LM, Chanock SJ, Armstrong GT, Morton LM. Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors. Nat Med 2024; 30:690-698. [PMID: 38454124 PMCID: PMC11029534 DOI: 10.1038/s41591-024-02837-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 01/26/2024] [Indexed: 03/09/2024]
Abstract
Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.
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Affiliation(s)
- Todd M Gibson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Danielle M Karyadi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stephen W Hartley
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michael A Arnold
- Department of Pathology, Children's Hospital of Colorado, University of Colorado, Denver, CO, USA
| | | | - Miriam R Conces
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
| | - Rebecca M Howell
- Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vidushi Kapoor
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Wendy M Leisenring
- Cancer Prevention and Clinical Statistics Programs, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Joseph P Neglia
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Joshua N Sampson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lucie M Turcotte
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Gregory T Armstrong
- Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lindsay M Morton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Sun Q, Rowland BT, Chen J, Mikhaylova AV, Avery C, Peters U, Lundin J, Matise T, Buyske S, Tao R, Mathias RA, Reiner AP, Auer PL, Cox NJ, Kooperberg C, Thornton TA, Raffield LM, Li Y. Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI. Nat Commun 2024; 15:1016. [PMID: 38310129 PMCID: PMC10838303 DOI: 10.1038/s41467-024-45135-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 01/16/2024] [Indexed: 02/05/2024] Open
Abstract
Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods focus only on participants with distinct primary continental ancestry without accommodating recently-admixed individuals with mosaic continental ancestry backgrounds for different segments of their genomes. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed for admixed individuals. GAUDI explicitly models ancestry-differential effects while borrowing information across segments with shared ancestry in admixed genomes. We demonstrate marked advantages of GAUDI over other methods through comprehensive simulation and real data analyses for traits with associated variants exhibiting ancestral-differential effects. Leveraging data from the Women's Health Initiative study, we show that GAUDI improves PRS prediction of white blood cell count and C-reactive protein in African Americans by > 64% compared to alternative methods, and even outperforms PRS-CSx with large European GWAS for some scenarios. We believe GAUDI will be a valuable tool to mitigate disparities in PRS performance in admixed individuals.
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Affiliation(s)
- Quan Sun
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Bryce T Rowland
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Jiawen Chen
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Anna V Mikhaylova
- Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA
| | - Christy Avery
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Jessica Lundin
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Tara Matise
- Department of Genetics, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Steve Buyske
- Department of Statistics, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Ran Tao
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Rasika A Mathias
- Department of Medicine, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Alexander P Reiner
- Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA
| | - Paul L Auer
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Nancy J Cox
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Timothy A Thornton
- Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA
| | - Laura M Raffield
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yun Li
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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Nakase T, Guerra G, Ostrom QT, Ge T, Melin B, Wrensch M, Wiencke JK, Jenkins RB, Eckel-Passow JE, Glioma International Case-Control Study (GICC), Bondy ML, Francis SS, Kachuri L. Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.01.10.24301112. [PMID: 38260701 PMCID: PMC10802631 DOI: 10.1101/2024.01.10.24301112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to find efficient ways of capturing genetic risk factors using available germline data. Methods We developed a novel PRS (PRS-CS) that uses continuous shrinkage priors to model the joint effects of over 1 million polymorphisms on disease risk and compared it to an approach (PRS-CT) that selects a limited set of independent variants that reach genome-wide significance (P<5×10-8). PRS models were trained using GWAS results stratified by histological (10,346 cases, 14,687 controls) and molecular subtype (2,632 cases, 2,445 controls), and validated in two independent cohorts. Results PRS-CS was consistently more predictive than PRS-CT across glioma subtypes with an average increase in explained variance (R2) of 21%. Improvements were particularly pronounced for glioblastoma tumors, with PRS-CS yielding larger effect sizes (odds ratio (OR)=1.93, P=2.0×10-54 vs. OR=1.83, P=9.4×10-50) and higher explained variance (R2=2.82% vs. R2=2.56%). Individuals in the 95th percentile of the PRS-CS distribution had a 3-fold higher lifetime absolute risk of IDH mutant (0.63%) and IDH wildtype (0.76%) glioma relative to individuals with average PRS. PRS-CS also showed high classification accuracy for IDH mutation status among cases (AUC=0.895). Conclusions Our novel genome-wide PRS may improve the identification of high-risk individuals and help distinguish between prognostic glioma subtypes, increasing the potential clinical utility of germline genetics in glioma patient management.
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Affiliation(s)
- Taishi Nakase
- Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
| | - Geno Guerra
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Quinn T. Ostrom
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA
| | - Tian Ge
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Beatrice Melin
- Department of Radiation Sciences, Oncology Umeå University, Umeå, Sweden
| | - Margaret Wrensch
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
| | - John K. Wiencke
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Robert B. Jenkins
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Melissa L. Bondy
- Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Stephen S. Francis
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
- Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Linda Kachuri
- Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
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Barnett EJ, Onete DG, Salekin A, Faraone SV. Genomic Machine Learning Meta-regression: Insights on Associations of Study Features With Reported Model Performance. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2024; 21:169-177. [PMID: 38109236 DOI: 10.1109/tcbb.2023.3343808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2023]
Abstract
Many studies have been conducted with the goal of correctly predicting diagnostic status of a disorder using the combination of genomic data and machine learning. It is often hard to judge which components of a study led to better results and whether better reported results represent a true improvement or an uncorrected bias inflating performance. We extracted information about the methods used and other differentiating features in genomic machine learning models. We used these features in linear regressions predicting model performance. We tested for univariate and multivariate associations as well as interactions between features. Of the models reviewed, 46% used feature selection methods that can lead to data leakage. Across our models, the number of hyperparameter optimizations reported, data leakage due to feature selection, model type, and modeling an autoimmune disorder were significantly associated with an increase in reported model performance. We found a significant, negative interaction between data leakage and training size. Our results suggest that methods susceptible to data leakage are prevalent among genomic machine learning research, resulting in inflated reported performance. Best practice guidelines that promote the avoidance and recognition of data leakage may help the field avoid biased results.
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Zhan J, Cen W, Zhu J, Ye Y. Development of a Novel Lipid Metabolism-related Gene Prognostic Signature for Patients with Colorectal Cancer. Recent Pat Anticancer Drug Discov 2024; 19:209-222. [PMID: 37723964 DOI: 10.2174/1574892818666230731121815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/03/2023] [Accepted: 07/13/2023] [Indexed: 09/20/2023]
Abstract
BACKGROUND The purpose of this study was to explore the expression profiles of lipid metabolism-related genes in patients with Colorectal Cancer (CRC). METHODS The lipid metabolism statuses of CRC patients from The Cancer Genome Atlas (TCGA) were analyzed. Risk characteristics were constructed by univariate Cox regression and minimum Absolute contraction and Selection Operator (LASSO) Cox regression. A histogram was constructed based on factors such as age, sex, TNM stage, T stage, N stage, and risk score to provide a visual tool for clinicians to predict the probability of 1-year, 3-year, and 5-year OS for CRC patients. By determining Area Under Curve (AUC) values, the time-dependent Receiver Operating characteristic Curve (ROC) was used to evaluate the efficiency of our model in predicting prognosis. RESULTS A novel risk signal based on lipid metabolism-related genes was constructed to predict the survival of CRC patients. Risk characteristics were shown to be an independent prognostic factor in CRC patients (p <0.001). There were significant differences in the abundance and immune characteristics of tumor-filtering immune cells between high-risk and low-risk groups. The nomogram had a high potential for clinical application and the ROC AUC value was 0.827. Moreover, ROC analysis demonstrated that the nomogram model was more accurate to predict the survival of CRC patients than age, gender, stage and risk score. CONCLUSION In this study, we demonstrated a lipid metabolism-related genes prognosis biomarker associated with the tumor immune micro-environment in patients with CRC.
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Affiliation(s)
- Jing Zhan
- Department of Surgery, Wenzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang, 325000, China
| | - Wei Cen
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Junchang Zhu
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yunliang Ye
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
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Chen X, Heisser T, Cardoso R, Hibbert J, Hoffmeister M, Brenner H. Beyond familial risk: deriving risk-adapted starting ages of screening among people with a family history of colorectal cancer. Cancer Commun (Lond) 2023; 43:1377-1380. [PMID: 37874634 PMCID: PMC10693305 DOI: 10.1002/cac2.12499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/05/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023] Open
Affiliation(s)
- Xuechen Chen
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Medical Faculty HeidelbergHeidelberg UniversityHeidelbergGermany
| | - Thomas Heisser
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Rafael Cardoso
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Julia Hibbert
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Medical Faculty HeidelbergHeidelberg UniversityHeidelbergGermany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Division of Preventive OncologyGerman Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)HeidelbergGermany
- German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
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Ladabaum U, Ko CW. Colorectal Cancer Risk Prediction to Tailor Screening: Will We Embrace It or KISS It Goodbye? Clin Gastroenterol Hepatol 2023; 21:3236-3237. [PMID: 37100217 DOI: 10.1016/j.cgh.2023.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 04/28/2023]
Affiliation(s)
- Uri Ladabaum
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Cynthia W Ko
- Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington
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van den Puttelaar R, Meester RGS, Peterse EFP, Zauber AG, Zheng J, Hayes RB, Su YR, Lee JK, Thomas M, Sakoda LC, Li Y, Corley DA, Peters U, Hsu L, Lansdorp-Vogelaar I. Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data. Clin Gastroenterol Hepatol 2023; 21:3415-3423.e29. [PMID: 36906080 PMCID: PMC10491743 DOI: 10.1016/j.cgh.2023.03.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 02/22/2023] [Accepted: 03/01/2023] [Indexed: 03/13/2023]
Abstract
BACKGROUND & AIMS Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.
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Affiliation(s)
| | - Reinier G S Meester
- Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Elisabeth F P Peterse
- Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ann G Zauber
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jiayin Zheng
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Richard B Hayes
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York
| | - Yu-Ru Su
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Biostatistics Unit, Kaiser Permanente Washington Health Research Institute, Seattle, Washington
| | - Jeffrey K Lee
- Division of Research, Kaiser Permanente Northern California, Oakland, California; Department of Gastroenterology, Kaiser Permanente San Francisco, San Francisco, California
| | - Minta Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Yi Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, California; Department of Gastroenterology, Kaiser Permanente San Francisco, San Francisco, California
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Iris Lansdorp-Vogelaar
- Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands
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