|
1
|
Azari H, George M, Albracht-Schulte K. Gut Microbiota-microRNA Interactions and Obesity Pathophysiology: A Systematic Review of Integrated Studies. Int J Mol Sci 2024; 25:12836. [PMID: 39684547 DOI: 10.3390/ijms252312836] [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: 10/31/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Obesity is the fifth leading cause of death globally and its comorbidities put a high burden on societies and cause disability. In this review, we aim to summarize the interactions and crosstalk between gut microbiota and micro-RNA (miRNA) in obesity. We searched for the relevant literature through PubMed, Web of Science, Scopus, and Science Direct. The study design is registered in the international prospective register of systematic reviews (Prospero). According to the inclusion criteria, eight studies were eligible for assessment (two studies including human subjects and six studies including animal subjects). We report that the interactions of miRNA and gut microbiota in the context of obesity are diverse and in some cases tissue specific. However, the interactions mediate obesity-associated pathways including the inflammatory response, oxidative stress, insulin signaling, gut permeability, and lipogenesis. To mention the most meaningful results, the expression of adipose tissue miRNA-378a-3p/5p was associated with Bifidobacterium and Akkermansia abundance, the expression of hepatic miRNA-34a was related to the Firmicutes phylum, and the expression of miRNA-122-5p and miRNA-375 was associated with the Bacteroides genus. miRNA-microbiota-associated pathological pathways seem to provide an intricate, but promising field for future research directed toward the treatment of obesity and its comorbidities.
Collapse
Affiliation(s)
- Hushyar Azari
- Department of Kinesiology and Sport Management and Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| | - Megan George
- Department of Kinesiology and Sport Management and Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| | - Kembra Albracht-Schulte
- Department of Kinesiology and Sport Management and Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| |
Collapse
|
|
2
|
Ungvari Z, Fekete M, Varga P, Lehoczki A, Fekete JT, Ungvari A, Győrffy B. Overweight and obesity significantly increase colorectal cancer risk: a meta-analysis of 66 studies revealing a 25-57% elevation in risk. GeroScience 2024:10.1007/s11357-024-01375-x. [PMID: 39379738 DOI: 10.1007/s11357-024-01375-x] [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] [Received: 08/29/2024] [Accepted: 10/01/2024] [Indexed: 10/10/2024] Open
Abstract
The incidence of colorectal cancer (CRC) has been steadily rising, and obesity has been identified as a significant risk factor. Numerous studies suggest a strong correlation between excess body weight and increased risk of CRC, but comprehensive quantification through pooled analysis remains limited. This study aims to systematically review and meta-analyze the existing literature to evaluate the association between obesity and CRC risk, considering variations across sex and study designs. A systematic literature search was conducted in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify randomized controlled trials and human clinical trials from 1992 to 2024. Statistical analysis was performed using the https://metaanalysisonline.com web application using a random effects model to estimate the pooled hazard rates (HR). Forest plots, funnel plots, and Z-score plots were utilized to visualize results. We identified 52 clinical trials and 14 case-control studies, encompassing a total of 83,251,050 and 236,877 subjects, respectively. The pooled analysis indicated that obesity significantly increased the prevalence of CRC (HR = 1.36, 95% CI = 1.24-1.48, p < 0.01). This effect was consistent across sexes, with HRs of 1.57 (95% CI = 1.38-1.78, p = 0.01) for males and 1.25 (95% CI = 1.14-1.38, p < 0.01) for females. Case-control studies specifically showed an effect, but with marginal significance only (HR = 1.27, 95% CI = 0.98-1.65, p = 0.07). The Z-score plot indicated the need for additional analysis in the case-control group. A significant heterogeneity was observed across studies in all four settings. This meta-analysis provides robust evidence that obesity is a significant risk factor for colorectal cancer, with an overall hazard rate indicating a 36% increased risk. The effect is pronounced across both sexes, with males showing a slightly higher risk compared to females. Although case-control studies showed a weaker association, the overall trend supports the link between obesity and CRC. These results underscore the importance of public health interventions aimed at reducing obesity to potentially lower the risk of colorectal cancer.
Collapse
Affiliation(s)
- Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral College/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary
| | - Mónika Fekete
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary
| | - Peter Varga
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary
| | - Andrea Lehoczki
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary
| | - János Tibor Fekete
- Dept. of Bioinformatics, Semmelweis University, 1094, Budapest, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117, Budapest, Hungary
| | - Anna Ungvari
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary.
| | - Balázs Győrffy
- Dept. of Bioinformatics, Semmelweis University, 1094, Budapest, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117, Budapest, Hungary
- Dept. of Biophysics, Medical School, University of Pecs, 7624, Pecs, Hungary
| |
Collapse
|
|
3
|
Thomas RJ, Ali AH, Bolwell J, Butler R, Burke CA, Liska D, Macaron C. Metachronous Colorectal Neoplasia in Young Adults With Advanced Neoplasia Undergoing Colonoscopy: A Comparison of Risk by Age <45 Years Versus 45 to 49 Years. J Clin Gastroenterol 2024:00004836-990000000-00346. [PMID: 39213008 DOI: 10.1097/mcg.0000000000002072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND The risk of metachronous advanced colorectal neoplasia (mACRN) in young adults with advanced lesions at baseline colonoscopy is not well defined. AIMS To examine the risk for (mACRN) in adults <50 years old who had advanced neoplasia (AN) at baseline colonoscopy and determine factors associated with mACRN in these patients. METHOD Patients 18 to 49 years of age with ≥1 AN [tubular adenoma (TA) ≥10 mm or with villous features or high-grade dysplasia (HGD), sessile serrated lesion (SSL) ≥10 mm or with dysplasia, traditional serrated adenoma (TSA)] on baseline colonoscopy between 2011 and 2021 who had surveillance colonoscopy >6 months after their baseline examination were included. Outcomes were assessed based on age at baseline colonoscopy, <45 years versus 45 to 49 years, and by follow-up colonoscopy findings: (1) normal, (2) nonadvanced neoplasia (NAN), and (3) AN. RESULTS Three hundred sixty-six patients with AN underwent ≥1 surveillance colonoscopy: 310 (84.7%) <45 years versus 56 (15.3%) 45 to 49 years. The mean follow-up time was longer for the <45-year-olds versus the 45 to 49-year-olds (43±26.4 vs. 28.4±12.8 mo respectively, P<0.001). The absolute risk of mACRN was 13.5% in the <45 age group versus 16.1% in the 45 to 49 age group, P=0.28. The 3-year cumulative incidence rates of mACRN were comparable for patients <45 and 45 to 49 years old: 10% (95% CI: 10% to 42%) versus 20% (95% CI: 7% to 15%), P=0.065. BMI was the only risk factor associated with mACRN OR 1.045 [95% CI (1.001 to 1.09)]. CONCLUSIONS In our cohort of patients <50 years old with AN at baseline, mACRN occurred at a similar rate to that reported by guidelines in 50 years and older, suggesting that current recommended post polypectomy surveillance is appropriate for this age group. BMI was independently associated with mACRN. Future studies should examine how weight management in patients with high BMI mitigates the recurrence of advanced neoplasia.
Collapse
Affiliation(s)
- Raj Jessica Thomas
- Department of Internal Medicine, Cleveland Clinic Akron General, Akron, OH
| | - Adel Hajj Ali
- Department of Internal Medicine, Indiana University, Indianapolis, IN
| | - Jacquelyn Bolwell
- Gastroenterology and Hepatology, Digestive Disease and Surgery Institute
| | | | - Carol A Burke
- Gastroenterology and Hepatology, Digestive Disease and Surgery Institute
- Young onset colorectal cancer center
- Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - David Liska
- Young onset colorectal cancer center
- Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - Carole Macaron
- Gastroenterology and Hepatology, Digestive Disease and Surgery Institute
- Young onset colorectal cancer center
| |
Collapse
|
|
4
|
Shan J, Li X, Sun R, Yao Y, Sun Y, Kuang Q, Dai X, Sun Y. Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via regulating lipidome metabolic reprogramming. J Exp Clin Cancer Res 2024; 43:227. [PMID: 39148124 PMCID: PMC11328492 DOI: 10.1186/s13046-024-03154-0] [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: 04/20/2024] [Accepted: 08/04/2024] [Indexed: 08/17/2024] Open
Abstract
BACKGROUND The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients. METHODS Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. RESULTS: To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis. CONCLUSIONS We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach.
Collapse
Affiliation(s)
- Junqi Shan
- Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Xinyu Li
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261000, China
| | - Runqi Sun
- School of Clinical Medicine, Jining Medical University, Jining, Shandong, 272000, China
| | - Yao Yao
- Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Yan Sun
- Key Laboratory of Biorheological Science and Technology, Chongqing University, College of Bioengineering, Ministry of Education, Chongqing University, Chongqing, 400030, PR China
| | - Qin Kuang
- Key Laboratory of Biorheological Science and Technology, Chongqing University, College of Bioengineering, Ministry of Education, Chongqing University, Chongqing, 400030, PR China
| | - Xianling Dai
- Key Laboratory of Biorheological Science and Technology, Chongqing University, College of Bioengineering, Ministry of Education, Chongqing University, Chongqing, 400030, PR China
| | - Yanlai Sun
- Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
| |
Collapse
|
|
5
|
O'Sullivan DE, Ruan Y, Farah E, Hutchinson JM, Hilsden RJ, Brenner DR. Risk factors for early-onset colorectal cancer: A Canadian prospective cohort study. Cancer Epidemiol 2024; 91:102578. [PMID: 38749340 DOI: 10.1016/j.canep.2024.102578] [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: 01/26/2024] [Revised: 04/02/2024] [Accepted: 04/23/2024] [Indexed: 07/16/2024]
Abstract
PURPOSE The incidence of early-onset (<50 years of age) colorectal cancer (eoCRC) has been steadily increasing in high-income countries including Canada. Despite this increase in incidence, the etiology of eoCRC remains unclear and prospective cohort studies of potential risk factors are limited. METHODS We examined two prospective cohorts of healthy individuals (<50 years of age) who completed baseline questionnaires in the Ontario Health Study and Alberta's Tomorrow Project. We examined the associations between demographic characteristics, chronic health conditions, and lifestyle behaviours with the development of eoCRC using Cox proportional hazard models. Cohorts were analyzed separately and hazard ratios for each risk factor were pooled with random effects meta-analyses. RESULTS During an average follow-up of 6.63 years, 98 eoCRC cases occurred among study participants (n=127,852). A family history of CRC alone or with a history of other cancer types was associated with an increased risk of developing eoCRC (HR: 2.76, 95% CI: 1.43-5.32), but a family history of a non-CRC cancer only was not (HR: 1.18, 95% CI: 0.61-2.30). Heavy smokers (≥ 10 pack-years) at baseline had a higher risk of eoCRC compared to non-smokers (HR: 1.87, 95% CI: 1.00-3.52). Sex, socioeconomic factors, diabetes, alcohol consumption, among other factors were not significantly associated with the risk of eoCRC. CONCLUSION Our findings indicate that specific CRC risk factors are also associated with developing eoCRC. The data in the study offers valuable insights that could be integrated in future meta-analyses. Additional prospective cohort studies are required to understand the etiology of eoCRC.
Collapse
Affiliation(s)
- Dylan E O'Sullivan
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta T2N 1N4, Canada; Department of Oncology, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
| | - Yibing Ruan
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta T2N 1N4, Canada; Department of Oncology, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Eliya Farah
- Department of Oncology, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - John M Hutchinson
- Department of Oncology, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Robert J Hilsden
- Department of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Darren R Brenner
- Department of Oncology, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| |
Collapse
|
|
6
|
Oliveira ML, Biggers A, Oddo VM, Yanez B, Booms E, Sharp L, Naylor K, Wolf PG, Tussing-Humphreys L. A Perspective Review on Diet Quality, Excess Adiposity, and Chronic Psychosocial Stress and Implications for Early-Onset Colorectal Cancer. J Nutr 2024; 154:1069-1079. [PMID: 38453027 PMCID: PMC11007745 DOI: 10.1016/j.tjnut.2024.03.002] [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: 01/28/2024] [Revised: 02/23/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Although the overall incidence of CRC has been decreasing over the past 40 y, early-onset colorectal cancer (EOCRC), which is defined as a CRC diagnosis in patients aged >50 y has increased. In this Perspective, we highlight and summarize the association between diet quality and excess adiposity, and EOCRC. We also explore chronic psychosocial stress (CPS), a less investigated modifiable risk factor, and EOCRC. We were able to show that a poor-quality diet, characterized by a high intake of sugary beverages and a Western diet pattern (high intake of red and processed meats, refined grains, and foods with added sugars) can promote risk factors associated with EOCRC development, such as an imbalance in the composition and function of the gut microbiome, presence of chronic inflammation, and insulin resistance. Excess adiposity, particularly obesity onset in early adulthood, is a likely contributor of EOCRC. Although the research is sparse examining CPS and CRC/EOCRC, we describe likely pathways linking CPS to tumorigenesis. Although additional research is needed to understand what factors are driving the uptick in EOCRC, managing body weight, improving diet quality, and mitigating psychosocial stress, may play an important role in reducing an individual's risk of EOCRC.
Collapse
Affiliation(s)
- Manoela Lima Oliveira
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, United States.
| | - Alana Biggers
- College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Vanessa M Oddo
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, United States
| | - Betina Yanez
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Emily Booms
- Department of Biology, Northeastern Illinois University, Chicago, IL, United States
| | - Lisa Sharp
- Institute for Health Research and Policy, University of Illinois at Chicago, Chicago, IL, United States
| | - Keith Naylor
- College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Patricia G Wolf
- Department of Nutrition Science, Purdue University, West Lafayette, IN, United States
| | - Lisa Tussing-Humphreys
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, United States
| |
Collapse
|
|
7
|
Gupta S, May FP, Kupfer SS, Murphy CC. Birth Cohort Colorectal Cancer (CRC): Implications for Research and Practice. Clin Gastroenterol Hepatol 2024; 22:455-469.e7. [PMID: 38081492 PMCID: PMC11304405 DOI: 10.1016/j.cgh.2023.11.040] [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: 09/21/2023] [Revised: 11/21/2023] [Accepted: 11/28/2023] [Indexed: 01/06/2024]
Abstract
Colorectal cancer (CRC) epidemiology is changing due to a birth cohort effect, first recognized by increasing incidence of early onset CRC (EOCRC, age <50 years). In this paper, we define "birth cohort CRC" as the observed phenomenon, among individuals born 1960 and later, of increasing CRC risk across successive birth cohorts, rising EOCRC incidence, increasing incidence among individuals aged 50 to 54 years, and flattening of prior decreasing incidence among individuals aged 55 to 74 years. We demonstrate birth cohort CRC is associated with unique features, including increasing rectal cancer (greater than colon) and distant (greater than local) stage CRC diagnosis, and increasing EOCRC across all racial/ethnic groups. We review potential risk factors, etiologies, and mechanisms for birth cohort CRC, using EOCRC as a starting point and describing importance of viewing these through the lens of birth cohort. We also outline implications of birth cohort CRC for epidemiologic and translational research, as well as current clinical practice. We postulate that recognition of birth cohort CRC as an entity-including and extending beyond rising EOCRC-can advance understanding of risk factors, etiologies, and mechanisms, and address the public health consequences of changing CRC epidemiology.
Collapse
Affiliation(s)
- Samir Gupta
- Section of Gastroenterology, Jennifer Moreno San Diego VA Medical Center, San Diego, California; Division of Gastroenterology, Department of Medicine, and Moores Cancer Center, University of California, La Jolla, California.
| | - Folasade P May
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California; UCLA Kaiser Permanente Center for Health Equity, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
| | - Sonia S Kupfer
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Caitlin C Murphy
- Department of Health Promotion & Behavioral Sciences, University of Texas Health Science Center at Houston (UTHealth Houston) School of Public Health, Houston, Texas
| |
Collapse
|
|
8
|
Xiao G, Zheng Y, Chen H, Luo M, Yang C, Ren D, Qin P, Zhang H, Lin H. Single-cell transcriptome analysis reveals immunosuppressive landscape in overweight and obese colorectal cancer. J Transl Med 2024; 22:134. [PMID: 38311726 PMCID: PMC10838453 DOI: 10.1186/s12967-024-04921-5] [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: 10/09/2023] [Accepted: 01/20/2024] [Indexed: 02/06/2024] Open
Abstract
BACKGROUND Overweight and obesity are established risk factors for various types of cancers including colorectal cancer (CRC). However the underlying molecular mechanisms remain unclear. An in-depth understanding of the oncologic characteristics of overweight and obese CRC at the single-cell level can provide valuable insights for the development of more effective treatment strategies for CRC. METHODS We conducted single-cell RNA sequencing (scRNA-seq) analysis on tumor and adjacent normal colorectal samples from 15 overweight/obese and 15 normal-weight CRC patients. Immunological and metabolic differences between overweight/obese CRC and non-obese CRC were characterized. RESULTS We obtained single-cell transcriptomics data from a total of 192,785 cells across all samples. By evaluating marker gene expression patterns, we annotated nine main cell types in the CRC ecosystem. Specifically, we found that the cytotoxic function of effector T cells and NK cells was impaired in overweight/obese CRC compared with non-obese CRC, relating to its metabolic dysregulation. CD4+T cells in overweight/obese CRC exhibited higher expression of immune checkpoint molecules. The antigen-presenting ability of DCs and B cells is down-regulated in overweight/obese CRC, which may further aggravate the immunosuppression of overweight/obese CRC. Additionally, dysfunctional stromal cells were identified, potentially promoting invasion and metastasis in overweight/obese CRC. Furthermore, we discovered the up-regulated metabolism of glycolysis and lipids of tumor cells in overweight/obese CRC, which may impact the metabolism and function of immune cells. We also identified inhibitory interactions between tumor cells and T cells in overweight/obese CRC. CONCLUSIONS The study demonstrated that overweight/obese CRC has a more immunosuppressive microenvironment and distinct metabolic reprogramming characterized by increased of glycolysis and lipid metabolism. These findings may have implications for the development of novel therapeutic strategies for overweight/obese CRC patients.
Collapse
Affiliation(s)
- Guozhong Xiao
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Yihui Zheng
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Huaxian Chen
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Minyi Luo
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Chaoxin Yang
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Donglin Ren
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Pengfei Qin
- BGI Research, Shenzhen, 518083, China.
- BGI Research, Chongqing, 401329, China.
| | - Heng Zhang
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
| | - Hongcheng Lin
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
| |
Collapse
|
|
9
|
Isah Tsamiya R, Mohd Nafi SN, Che Jalil NA, Mat Zin AA. The Clinicopathological Characteristics of Young-Onset Versus Adult-Onset Colorectal Cancer: A Tertiary Hospital-Based Study. Malays J Med Sci 2024; 31:200-211. [PMID: 38456100 PMCID: PMC10917589 DOI: 10.21315/mjms2024.31.1.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 06/02/2023] [Indexed: 03/09/2024] Open
Abstract
Background The prevalence of colorectal cancer (CRC) among young individuals is rising worldwide, especially in Malaysia. Investigations are currently employed to distinguish the features of young-onset CRC (YOCRC) from adult-onset CRC (AOCRC). This study aimed to compare the characteristics of patients with YOCRC and AOCRC diagnosed at Hospital Universiti Sains Malaysia (HUSM). Methods This was a retrospective study of CRC cases from January 2013 to December 2021. The details of YOCRC (< 50 years old) and AOCRC (≥ 50 years old) patients were retrieved from the laboratory system and medical records. The Pearson's chi-square test, Fisher's exact test and multiple logistic regression were used to compare the AOCRC and YOCRC cases. Statistical significance was defined at a P-value of ≤ 0.05. Results The AOCRC (254/319, 79.6%) was more prevalent than YOCRC (65/319, 20.4%), with a predominance of males (53.9%) and Malay sub-population (90.2%). AOCRC and YOCRC shared similarities in left-sided location, high occurrence of adenocarcinoma with moderately differentiated histology and advanced stage of diagnosis. More patients with YOCRC (23.1%) had a family history of cancer than patients with AOCRC. YOCRC also differed from AOCRC by having more specific histological subtypes, such as mucinous adenocarcinoma (15.4%) and signet ring carcinoma (6.2%). In addition, patients with YOCRC commonly presented with a low density of tumour-infiltrating lymphocytes (TILs) (60%). Multiple logistic regression showed a family history of CRC (adjusted odds ratio [AOR] = 3.75, P = 0.003) and histological type (AOR = 15.21, P < 0.001) are more likely to cause YOCRC than diabetes (AOR = 0.06, P < 0.001) and hypertension (AOR = 0.14, P < 0.001) comorbidities, which are associated with AOCRC. Conclusion Our descriptive study presented the epidemiological and histopathological characteristics of AOCRC and YOCRC in HUSM, providing current information on distinguishing features between the groups.
Collapse
Affiliation(s)
- Rilwanu Isah Tsamiya
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Siti Norasikin Mohd Nafi
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Nur Asyilla Che Jalil
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Kelantan, Malaysia
| | - Anani Aila Mat Zin
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Kelantan, Malaysia
| |
Collapse
|
|
10
|
Lingas EC. Early-Onset Colon Cancer: A Narrative Review of Its Pathogenesis, Clinical Presentation, Treatment, and Prognosis. Cureus 2023; 15:e45404. [PMID: 37854763 PMCID: PMC10579844 DOI: 10.7759/cureus.45404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2023] [Indexed: 10/20/2023] Open
Abstract
Colon cancer remains a leading cause of cancer-related deaths, and there has been a rise in the incidence of early-onset colon cancer or colon cancer diagnosed before the age of 50 years old. Early-onset colon cancer has several differences in clinical presentation, as well as histopathology, genetic alteration, and molecular profiling. Early-onset colon cancer can be differentiated into familial type that includes hereditary familial syndrome and sporadic type. Demographic variance also exists in both developing and developed countries. Due to the rising incidence of colon cancer diagnosed in younger age, it is imperative to examine the available evidence regarding the mortality rate of early-onset colon cancer. Colon cancer is affected by numerous modifiable and non-modifiable risk factors. Increasing obesity and lifestyle disorders in the younger population, such as smoking, may influence this increasing trend. There are existing guidelines for colon cancer screening in both average-risk and high-risk individuals. This narrative review aims to highlight the pathogenesis of early-onset CRC; its clinical presentation, treatment, prognosis; and how it differs from late-onset CRC.
Collapse
Affiliation(s)
- Elvina C Lingas
- Hospital Medicine, New York University (NYU) Langone Health Long Island Community Hospital, Patchogue, USA
| |
Collapse
|
|
11
|
Li S, Keenan JI, Shaw IC, Frizelle FA. Could Microplastics Be a Driver for Early Onset Colorectal Cancer? Cancers (Basel) 2023; 15:3323. [PMID: 37444433 DOI: 10.3390/cancers15133323] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/12/2023] [Accepted: 06/18/2023] [Indexed: 07/15/2023] Open
Abstract
Introduction: The incidence of colorectal cancer in those under 50 years of age (early onset colorectal cancer (EOCRC)) is increasing throughout the world. This has predominantly been an increase in distal colonic and rectal cancers, which are biologically similar to late onset colorectal cancer (LOCRC) but with higher rates of mucinous or signet ring histology, or poorly differentiated cancers. The epidemiology of this change suggests that it is a cohort effect since 1960, and is most likely driven by an environmental cause. We explore the possible role of microplastics as a driver for this change. Review: The development of sporadic colorectal cancer is likely facilitated by the interaction of gut bacteria and the intestinal wall. Normally, a complex layer of luminal mucus provides colonocytes with a level of protection from the effects of these bacteria and their toxins. Plastics were first developed in the early 1900s. After 1945 they became more widely used, with a resultant dramatic increase in plastic pollution and their breakdown to microplastics. Microplastics (MPs) are consumed by humans from an early age and in increasingly large quantities. As MPs pass through the gastrointestinal tract they interact with the normal physiological mechanism of the body, particularly in the colon and rectum, where they may interact with the protective colonic mucus layer. We describe several possible mechanisms of how microplastics may disrupt this mucus layer, thus reducing its protective effect and increasing the likelihood of colorectal cancer. Conclusions: The epidemiology of increase in EOCRC suggests an environmental driver. This increase in EOCRC matches the time sequence in which we could expect to see an effect of rapid increase of MPs in the environment and, as such, we have explored possible mechanisms for this effect. We suggest that it is possible that the MPs damage the barrier integrity of the colonic mucus layer, thus reducing its protective effect. MPs in CRC pathogenesis warrants further investigation. Future directions: Further clarification needs to be sought regarding the interaction between MPs, gut microbiota and the mucus layer. This will need to be modelled in long-term animal studies to better understand how chronic consumption of environmentally-acquired MPs may contribute to an increased risk of colorectal carcinogenesis.
Collapse
Affiliation(s)
- Shelley Li
- Department of Surgery, University of Otago Christchurch, Christchurch 8011, New Zealand
| | - Jacqueline I Keenan
- Department of Surgery, University of Otago Christchurch, Christchurch 8011, New Zealand
| | - Ian C Shaw
- School of Physical & Chemical Sciences, University of Canterbury, Christchurch 8041, New Zealand
| | - Frank A Frizelle
- Department of Surgery, University of Otago Christchurch, Christchurch 8011, New Zealand
| |
Collapse
|
|
12
|
Wang SY, Zhang WS, Jiang CQ, Jin YL, Zhu T, Zhu F, Xu L. Association of novel and conventional obesity indices with colorectal cancer risk in older Chinese: a 14-year follow-up of the Guangzhou Biobank Cohort Study. BMC Cancer 2023; 23:286. [PMID: 36991401 DOI: 10.1186/s12885-023-10762-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Abstract
Background
Visceral adiposity index (VAI) and a body shape index (ABSI) were newly developed indices for visceral fat mass. Whether they are superior to conventional obesity indices in predicting colorectal cancer (CRC) remains unclear. We examined the associations of VAI and ABSI with CRC risk, and investigated their performance in discriminating CRC risk compared with conventional obesity indices in the Guangzhou Biobank Cohort Study.
Methods
A total of 28,359 participants aged 50 + years without cancer history at baseline (2003-8) were included. CRC were identified from the Guangzhou Cancer Registry. Cox proportional hazards regression was used to assess the association of obesity indices with the CRC risk. Discriminative abilities of obesity indices were assessed using Harrell’s C-statistic.
Results
During an average follow-up of 13.9 (standard deviation = 3.6) years, 630 incident CRC cases were recorded. After adjusting for potential confounders, the hazard ratio (95% confidence interval) of incident CRC for per standard deviation increment in VAI, ABSI, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) was 1.04 (0.96, 1.12), 1.13 (1.04, 1.22), 1.08 (1.00, 1.17), 1.15 (1.06, 1.24), 1.16 (1.08, 1.25)and 1.13 (1.04, 1.22), respectively. Similar results for colon cancer were found. However, the associations of obesity indices with risk of rectal cancer were non-significant. All obesity indices showed similar discriminative abilities (C-statistics from 0.640 to 0.645), with WHR showing the highest whilst VAI and BMI the lowest.
Conclusions
ABSI, but not VAI, was positively associated with a higher risk of CRC. However, ABSI was not superior to the conventional abdominal obesity indices in predicting CRC.
Collapse
|
|
13
|
Marx O, Mankarious M, Yochum G. Molecular genetics of early-onset colorectal cancer. World J Biol Chem 2023; 14:13-27. [PMID: 37034132 PMCID: PMC10080548 DOI: 10.4331/wjbc.v14.i2.13] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/20/2022] [Accepted: 02/13/2023] [Indexed: 03/24/2023] Open
Abstract
Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts.
Collapse
Affiliation(s)
- Olivia Marx
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Marc Mankarious
- Department of Surgery, Division of Colon & Rectal Surgery, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA 17033, United States
| | - Gregory Yochum
- Department of Biochemistry & Molecular Biology & Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| |
Collapse
|
|
14
|
Florensa D, Mateo J, Solsona F, Galván L, Mesas M, Piñol R, Espinosa-Leal L, Godoy P. Acetylsalicylic Acid Effect in Colorectal Cancer Taking into Account the Role of Tobacco, Alcohol and Excess Weight. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:ijerph20054104. [PMID: 36901115 PMCID: PMC10001481 DOI: 10.3390/ijerph20054104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/17/2023] [Accepted: 02/22/2023] [Indexed: 06/13/2023]
Abstract
Excess weight, smoking and risky drinking are preventable risk factors for colorectal cancer (CRC). However, several studies have reported a protective association between aspirin and the risk of CRC. This article looks deeper into the relationships between risk factors and aspirin use with the risk of developing CRC. We performed a retrospective cohort study of CRC risk factors and aspirin use in persons aged >50 years in Lleida province. The participants were inhabitants with some medication prescribed between 2007 and 2016 that were linked to the Population-Based Cancer Registry to detect CRC diagnosed between 2012 and 2016. Risk factors and aspirin use were studied using the adjusted HR (aHR) with 95% confidence intervals (CI) using a Cox proportional hazard model. We included 154,715 inhabitants of Lleida (Spain) aged >50 years. Of patients with CRC, 62% were male (HR = 1.8; 95% CI: 1.6-2.2), 39.5% were overweight (HR = 2.8; 95% CI: 2.3-3.4) and 47.3% were obese (HR = 3.0; 95% CI: 2.6-3.6). Cox regression showed an association between aspirin and CRC (aHR = 0.7; 95% CI: 0.6-0.8), confirming a protective effect against CRC and an association between the risk of CRC and excess weight (aHR = 1.4; 95% CI: 1.2-1.7), smoking (aHR = 1.4; 95% CI: 1.3-1.7) and risky drinking (aHR = 1.6; 95% CI: 1.2-2.0). Our results show that aspirin use decreased the risk of CRC and corroborate the relationship between overweight, smoking and risky drinking and the risk of CRC.
Collapse
Affiliation(s)
- Didac Florensa
- Department of Computer Engineering and Digital Design, University of Lleida, Jaume II 69, 25001 Lleida, Spain
- Population Cancer Registry in Lleida, Santa Maria University Hospital, Av. Alcalde Rovira Roure 44, 25198 Lleida, Spain
| | - Jordi Mateo
- Department of Computer Engineering and Digital Design, University of Lleida, Jaume II 69, 25001 Lleida, Spain
| | - Francesc Solsona
- Department of Computer Engineering and Digital Design, University of Lleida, Jaume II 69, 25001 Lleida, Spain
| | - Leonardo Galván
- Pharmacy Unit, Catalan Health Service, Av. Alcalde Rovira Roure 2, 25006 Lleida, Spain
| | - Miquel Mesas
- SAP-Argos Department, Santa Maria University Hospital, Av. Alcalde Rovira Roure 44, 25198 Lleida, Spain
| | - Ramon Piñol
- Catalan Health Service, Department of Health, Av. Alcalde Rovira Roure 2, 25006 Lleida, Spain
| | - Leonardo Espinosa-Leal
- Graduate School and Research, Arcada University of Applied Science, Jan-Magnus Janssonin Aukio 1, 00550 Helsinki, Finland
| | - Pere Godoy
- Population Cancer Registry in Lleida, Santa Maria University Hospital, Av. Alcalde Rovira Roure 44, 25198 Lleida, Spain
- Lleida Biomedical Research Institute, Av. Alcalde Rovira Roure 80, 25198 Lleida, Spain
- CIBER Epidemiology and Public Health (CIBERESP), Health Institute Carlos III, 28029 Madrid, Spain
| |
Collapse
|
|
15
|
Li H, Chen X, Hoffmeister M, Brenner H. Associations of smoking with early- and late-onset colorectal cancer. JNCI Cancer Spectr 2023; 7:7033469. [PMID: 36759940 PMCID: PMC9940696 DOI: 10.1093/jncics/pkad004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/21/2022] [Accepted: 01/06/2023] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Incidence of colorectal cancer (CRC) in younger adults is increasing in many countries. Smoking is an established risk factor of CRC risk, but evidence on its impact on early-onset CRC (EOCRC) risk is limited. We aimed to evaluate the association of smoking exposure with EOCRC and compare it with late-onset CRC (LOCRC). METHODS Smoking history and other known or suspected CRC risk factors were ascertained in detail in personal interviews among 6264 CRC patients and 6866 controls (frequency matched for age, sex, and county of residence) who were recruited in 2003-2020 in the DACHS study (Darmkrebs: Chancen der Verhütung durch Screening [German]; Colorectal Cancer: Chances for Prevention Through Screening [English]), a population-based case-control study from Germany. Associations of smoking with EOCRC (<55 years, 724 cases, 787 controls) and LOCRC (≥55years, 5540 cases, 6079 controls) were estimated using multiple logistic regression. RESULTS Smoking exposure was much higher among EOCRC cases than among controls, and strong associations of smoking were observed for both EOCRC and LOCR. Adjusted odds ratios for EOCRC and LOCRC were as follows: current smoking: 1.57 (95% confidence interval [CI] = 1.20 to 2.04, P < .001) and 1.46 (95% CI = 1.28 to 1.67, P < .001); former smoking: 1.39 (95% CI = 1.07 to 1.81, P = .01) and 1.24 (95% CI = 1.13 to 1.36, P < .001); per 10 pack-years: 1.15 (95% CI = 1.05 to 1.27, P < .001) and 1.05 (95% CI = 1.03 to 1.08, P < .001). These patterns were similar for colon and rectum cancer and for early- and late-stage CRC. CONCLUSION Smoking is a strong risk factor for both EOCRC and LOCRC.
Collapse
Affiliation(s)
- Hengjing Li
- 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,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
- Correspondence to: Hermann Brenner, MD, MPH, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany (e-mail: )
| |
Collapse
|
|
16
|
Ugai T, Sasamoto N, Lee HY, Ando M, Song M, Tamimi RM, Kawachi I, Campbell PT, Giovannucci EL, Weiderpass E, Rebbeck TR, Ogino S. Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat Rev Clin Oncol 2022; 19:656-673. [PMID: 36068272 PMCID: PMC9509459 DOI: 10.1038/s41571-022-00672-8] [Citation(s) in RCA: 252] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2022] [Indexed: 02/07/2023]
Abstract
Over the past several decades, the incidence of early-onset cancers, often defined as cancers diagnosed in adults <50 years of age, in the breast, colorectum, endometrium, oesophagus, extrahepatic bile duct, gallbladder, head and neck, kidney, liver, bone marrow, pancreas, prostate, stomach and thyroid has increased in multiple countries. Increased use of screening programmes has contributed to this phenomenon to a certain extent, although a genuine increase in the incidence of early-onset forms of several cancer types also seems to have emerged. Evidence suggests an aetiological role of risk factor exposures in early life and young adulthood. Since the mid-20th century, substantial multigenerational changes in the exposome have occurred (including changes in diet, lifestyle, obesity, environment and the microbiome, all of which might interact with genomic and/or genetic susceptibilities). However, the effects of individual exposures remain largely unknown. To study early-life exposures and their implications for multiple cancer types will require prospective cohort studies with dedicated biobanking and data collection technologies. Raising awareness among both the public and health-care professionals will also be critical. In this Review, we describe changes in the incidence of early-onset cancers globally and suggest measures that are likely to reduce the burden of cancers and other chronic non-communicable diseases.
Collapse
Affiliation(s)
- Tomotaka Ugai
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Naoko Sasamoto
- Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA
- Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA, USA
| | - Hwa-Young Lee
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Institute of Convergence Science, Convergence Science Academy, Yonsei University, Seoul, Republic of Korea
| | - Mariko Ando
- Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Rulla M Tamimi
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Ichiro Kawachi
- Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Peter T Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Timothy R Rebbeck
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
- Zhu Family Center for Global Cancer Prevention, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA.
| |
Collapse
|
|
17
|
Yuan Y, Tong D, Liu M, Lu H, Shen F, Shi X. An MRI-based pelvimetry nomogram for predicting surgical difficulty of transabdominal resection in patients with middle and low rectal cancer. Front Oncol 2022; 12:882300. [PMID: 35957878 PMCID: PMC9357897 DOI: 10.3389/fonc.2022.882300] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Objective The current work aimed to develop a nomogram comprised of MRI-based pelvimetry and clinical factors for predicting the difficulty of rectal surgery for middle and low rectal cancer (RC). Methods Consecutive mid to low RC cases who underwent transabdominal resection between June 2020 and August 2021 were retrospectively enrolled. Univariable and multivariable logistic regression analyses were carried out for identifying factors (clinical factors and MRI-based pelvimetry parameters) independently associated with the difficulty level of rectal surgery. A nomogram model was established with the selected parameters for predicting the probability of high surgical difficulty. The predictive ability of the nomogram model was assessed by the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Results A total of 122 cases were included. BMI (OR = 1.269, p = 0.006), pelvic inlet (OR = 1.057, p = 0.024) and intertuberous distance (OR = 0.938, p = 0.001) independently predicted surgical difficulty level in multivariate logistic regression analysis. The nomogram model combining these predictors had an area under the ROC curve (AUC) of 0.801 (95% CI: 0.719–0.868) for the prediction of a high level of surgical difficulty. The DCA suggested that using the nomogram to predict surgical difficulty provided a clinical benefit. Conclusions The nomogram model is feasible for predicting the difficulty level of rectal surgery, utilizing MRI-based pelvimetry parameters and clinical factors in mid to low RC cases.
Collapse
Affiliation(s)
- Yuan Yuan
- Department of Radiology, Changhai Hospital, Shanghai, China
| | - Dafeng Tong
- Department of Colorectal Surgery, Changhai Hospital, Shanghai, China
| | - Minglu Liu
- Department of Radiology, Changhai Hospital, Shanghai, China
| | - Haidi Lu
- Department of Radiology, Changhai Hospital, Shanghai, China
| | - Fu Shen
- Department of Radiology, Changhai Hospital, Shanghai, China
- *Correspondence: Xiaohui Shi, ; Fu Shen,
| | - Xiaohui Shi
- Department of Colorectal Surgery, Changhai Hospital, Shanghai, China
- *Correspondence: Xiaohui Shi, ; Fu Shen,
| |
Collapse
|
|
18
|
O'Sullivan DE, Sutherland RL, Town S, Chow K, Fan J, Forbes N, Heitman SJ, Hilsden RJ, Brenner DR. Risk Factors for Early-Onset Colorectal Cancer: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2022; 20:1229-1240.e5. [PMID: 33524598 DOI: 10.1016/j.cgh.2021.01.037] [Citation(s) in RCA: 168] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/18/2021] [Accepted: 01/24/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Despite the widespread increase in the incidence of early-onset colorectal cancer (EoCRC), the reasons for this increase remain unclear. The objective of this study was to determine risk factors for the development of EoCRC. METHODS We conducted a systematic literature review and meta-analysis of studies examining non-genetic risk factors for EoCRC, including demographic factors, comorbidities, and lifestyle factors. Random effects meta-analyses were conducted for risk factors that were examined in at least three studies. Heterogeneity was investigated using the Q-test and I2 statistic. RESULTS From 3304 initial citations, 20 studies were included in this review. Significant risk factors for EoCRC included CRC history in a first-degree relative (RR 4.21, 95% CI 2.61-6.79), hyperlipidemia (RR 1.62, 95% CI 1.22-2.13), obesity (RR 1.54, 95% CI 1.01-2.35), and alcohol consumption (high vs. non-drinkers) (RR 1.71, 95% CI 1.62-1.80). While smoking was suggestive as a risk factor, the association was not statistically significant (RR 1.35, 95% CI 0.81-2.25). With the exception of alcohol consumption, there was considerable heterogeneity among studies (I2 > 60%). Other potential risk factors included hypertension, metabolic syndrome, ulcerative colitis, chronic kidney disease, dietary factors, sedentary behaviour, and occupational exposure to organic dusts, but these were only examined in one or two studies. CONCLUSIONS The results of this study advance the understanding of the etiology of EoCRC. High-quality studies conducted on generalizable populations and that comprehensively examine risk factors for EoCRC are required to inform primary and secondary prevention strategies.
Collapse
Affiliation(s)
- Dylan E O'Sullivan
- Department of Community Health Sciences, University of Calgary, Calgary, AB; Department of Oncology, University of Calgary, Calgary, AB; Forzani & MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB
| | - R Liam Sutherland
- Department of Community Health Sciences, University of Calgary, Calgary, AB; Department of Oncology, University of Calgary, Calgary, AB; Forzani & MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB
| | - Susanna Town
- Forzani & MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB
| | - Kristian Chow
- Department of Community Health Sciences, University of Calgary, Calgary, AB
| | - Jeremy Fan
- Department of Community Health Sciences, University of Calgary, Calgary, AB
| | - Nauzer Forbes
- Department of Community Health Sciences, University of Calgary, Calgary, AB; Forzani & MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Steven J Heitman
- Department of Community Health Sciences, University of Calgary, Calgary, AB; Forzani & MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Robert J Hilsden
- Department of Community Health Sciences, University of Calgary, Calgary, AB; Forzani & MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Darren R Brenner
- Department of Community Health Sciences, University of Calgary, Calgary, AB; Department of Oncology, University of Calgary, Calgary, AB; Forzani & MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB.
| |
Collapse
|
|
19
|
Role of Perirectal Fat in the Carcinogenesis and Development of Early-Onset Rectal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:4061142. [PMID: 35368890 PMCID: PMC8965599 DOI: 10.1155/2022/4061142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/24/2022] [Accepted: 03/05/2022] [Indexed: 11/17/2022]
Abstract
Purpose The incidence of early-onset rectal cancer (EORC) has been increasing since the past decade, while its underlying cause remained unknown. This study was aimed at clarifying the relationship between perirectal fat area (PFA) and EORC. Patients and Methods. All patients with rectal cancer who received radical excision between January 2016 and December 2017 at our hospital were included. The fat series images of pelvic magnetic resonance imaging scans were obtained and PFA at the ischial spine level was calculated using the ImageJ software. Results A total of 303 patients were finally included and divided into two groups according to the median PFA: Group 1 (<20.2 cm2, n = 151) and Group 2 (≥20.2 cm2, n = 152). PFA positively correlated with body weight and body mass index. PFA increased with invasion depth, lymph node metastasis, TNM stage, tumor deposits, and vascular invasion. Patients with EORC had higher PFA than those with late-onset rectal cancer (LORC; P = 0.009). Among patients with stage I–III rectal cancers, those in Group 2 had significantly shorter disease-free survival (P = 0.010) and overall survival (P = 0.034) than those in Group 1, and PFA was an independent predictor of disease-free survival (OR: 1.683 [1.126-3.015], P = 0.035) and overall survival (OR: 1.678 [1.022-2.639], P = 0.046). Conclusions Patients with EORC had significantly higher PFA than those with LORC. PFA is positively correlated with T stage, N stage, TNM stage, tumor deposit, and vascular invasion and is an independent predictor of disease-free survival and overall survival. Therefore, perirectal fat may be involved in the carcinogenesis and development of EORC.
Collapse
|
|
20
|
Loomans-Kropp HA, Song Y, Gala M, Parikh AR, Van Seventer EE, Alvarez R, Hitchins MP, Shoemaker RH, Umar A. Methylated Septin9 (m SEPT9): A promising blood-based biomarker for the detection and screening of early-onset colorectal cancer. CANCER RESEARCH COMMUNICATIONS 2022; 2:90-98. [PMID: 35992328 PMCID: PMC9387652 DOI: 10.1158/2767-9764.crc-21-0142] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/20/2021] [Accepted: 02/01/2022] [Indexed: 06/15/2023]
Abstract
Early-onset colorectal cancer (EOCRC), defined as a diagnosis under age 50, is an emerging public health burden. As many of these individuals fall outside of screening guidelines, the development of a minimally invasive, accurate screening modality for this population is warranted. We evaluated the FDA-approved blood-based biomarker methylated Septin9 (mSEPT9) test as screening tool for EOCRC. EOCRC plasma, healthy plasma, and serum-free conditioned media from cancer cell lines was collected. Cell-free DNA (cfDNA) was isolated and bisulfite converted for use in the assay. mSEPT9 and ACTB measured using Epi proColon® V2.0. EOCRC plasma was collected at Massachusetts General Hospital (2005-2019) and controls were collected at the National Institutes of Health and by ZenBio Inc. (prior to 2019). Twenty-seven EOCRC cases, 48 healthy controls <50 years old, and 39 healthy controls ≥50 years old were included in this study. mSEPT9 was detected more frequently in EOCRC cases (88.9%) compared to healthy controls age <50 (4.2%) and ≥50 (15.4%), respectively (p<0.001). The sensitivity, specificity, positive predictive value, and negative predictive values of the mSEPT9 assay to detect EOCRC was 90.8% (95% CI: 84.7-96.9%), 88.9% (95% CI: 77.0-100.0%), 96.3% (95% CI: 92.3-100.0%), and 75.0% (95% CI 60.0-90.0%), respectively, compared to all healthy controls. mSEPT9 cfDNA level was an independent predictor of survival (p=0.02). mSEPT9 is a sensitive and specific biomarker for EOCRC detection. These results suggest that mSEPT9 may be useful in the detection of EOCRC, providing a minimally invasive method for screening in this growing population of CRC patients.
Collapse
Affiliation(s)
- Holli A. Loomans-Kropp
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, NCI, NIH, Rockville, Maryland
- Gastrointestinal and Other Cancers Research Group, Division of Cancer Prevention, NCI, NIH, Rockville, Maryland
| | - Yurong Song
- Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Manish Gala
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Aparna R. Parikh
- Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Emily E. Van Seventer
- Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Rocio Alvarez
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Megan P. Hitchins
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Robert H. Shoemaker
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, NIH, Rockville, Maryland
| | - Asad Umar
- Gastrointestinal and Other Cancers Research Group, Division of Cancer Prevention, NCI, NIH, Rockville, Maryland
| |
Collapse
|
|
21
|
Puzzono M, Mannucci A, Di Leo M, Zuppardo RA, Russo M, Ditonno I, Goni E, Notaristefano C, Azzolini F, Fanti L, Viale E, Elmore U, Pantaleo G, Cascinu S, Rosati R, Cavestro GM. Diet and Lifestyle Habits in Early-Onset Colorectal Cancer: A Pilot Case-Control Study. Dig Dis 2022; 40:710-718. [PMID: 35086089 DOI: 10.1159/000521932] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/12/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND Early-onset colorectal cancer (eoCRC), defined as a colorectal cancer (CRC) in patients younger than 50 years old, shows an increasing incidence worldwide in the latest years. The role of exogenous factors associated with CRC has been largely overlooked in eoCRC. Here, we conducted a case-control study to evaluate the diet and the lifestyle habits in an Italian population of patients with eoCRC, compared to age-matched healthy controls (HCs). METHODS We enrolled 118 subjects (47 cases, 71 controls) in a third-level academic hospital. We analyzed epidemiological features (age, sex, body mass index), lifestyle behaviors (smoking habits, physical activity, type of diet, use of dietary supplements), and eating habits (semiquantitative food-frequency questionnaire) in eoCRCs and HCs, covering the previous 5 years. RESULTS In our cohort, positive family history of CRC was significantly associated with the development of eoCRC (p = 0.004). Fresh meat (p = 0.003), processed meat (p < 0.001), dairy products (p = 0.013), and smoking (p = 0.0001) were significantly associated with eoCRC compared to controls. Other variables did not differ significantly between the two groups. CONCLUSION Fresh and processed meat, dairy products, and smoking could be considered significant risk factors for eoCRC, although further confirmation by international multicenter studies is desirable. Diet and smoking could be the main areas of future interventions for eoCRC primary prevention.
Collapse
Affiliation(s)
- Marta Puzzono
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Medical Biotechnologies Department, University of Siena, Siena, Italy
| | - Alessandro Mannucci
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Milena Di Leo
- Digestive Endoscopy Unit, ASST Santi Paolo e Carlo, Milan, Italy
| | - Raffaella A Zuppardo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Michele Russo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ilaria Ditonno
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Elisabetta Goni
- Medical Department II, University Hospital, Ludwig Maximilians-University, Munich, Germany
| | - Chiara Notaristefano
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Azzolini
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lorella Fanti
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Edi Viale
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ugo Elmore
- Department of Surgery, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Giuseppe Pantaleo
- UniSR-Social.Lab, Faculty of Psychology, Vita-Salute San Raffaele University, Milan, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Riccardo Rosati
- Department of Surgery, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
22
|
The Role of Diet and Lifestyle in Early-Onset Colorectal Cancer: A Systematic Review. Cancers (Basel) 2021; 13:cancers13235933. [PMID: 34885046 PMCID: PMC8657307 DOI: 10.3390/cancers13235933] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This systematic review sifted through the exogenous dietary and lifestyle risk factors associated with early-onset colorectal cancer, going through the putative involvement of these exogenous risk factors in epigenetic and microbiota modifications. Given the burden of early-onset colorectal cancer and its globally increasing trend with scant literature on its pathogenesis, we believe it would be of benefit to highlight the importance of further systematic and large studies. Indeed, dietary and lifestyle modification could complement colorectal screening for early-onset colorectal cancer prevention. Abstract The incidence of early-onset colorectal cancer, defined as colorectal cancer occurring in young adults under the age of 50, is increasing globally. Knowledge of the etiological factors in young adults is far from complete. Questionable eoCRCs’ exogenous factors are represented by processed meat, sugary drinks, alcohol, Western dietary pattern, overweight and obesity, physical inactivity, and smoking, though with heterogeneous results. Therefore, we performed a systematic review to summarize the current evidence on the role of diet and lifestyle as eoCRC risk factors. We systematically searched PubMed, Scopus, and EMBASE up to July 2021, for original studies evaluating diet, alcohol, physical activity, BMI, and smoking in eoCRC and included twenty-six studies. Indeed, the exogenous factors could represent modifiable key factors, whose recognition could establish areas of future interventions through public health strategies for eoCRC primary prevention. Additionally, we discussed the role of additional non-modifiable risk factors, and of epigenetic regulation and microbiota as mediators of the eoCRC triggered by diet and lifestyle.
Collapse
|
|
23
|
Makmun D, Simadibrata M, Abdullah M, Syam AF, Shatri H, Fauzi A, Renaldi K, Maulahela H, Utari AP, Pribadi RR, Muzellina VN, Nursyirwan SA. Colorectal cancer patients in a tertiary hospital in Indonesia: Prevalence of the younger population and associated factors. World J Clin Cases 2021; 9:9804-9814. [PMID: 34877319 PMCID: PMC8610908 DOI: 10.12998/wjcc.v9.i32.9804] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/15/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND An increasing trend in colorectal cancer (CRC) occurring at younger ages has been observed worldwide, even though incidence is declining in the general population. Most currently available guidelines still recommend CRC screening for older populations, despite an alarming rise in early-onset CRC incidence. Risk stratification is necessary to further determine the population most at risk for early-onset CRC. However, epidemiological data on related clinical characteristics and potential risk factors, especially in developing countries, have not been widely reported. AIM To investigate the prevalence, demographics, clinicopathologic features, and associated factors of young-onset CRC patients in a tertiary hospital in Indonesia. METHODS Patients undergoing colonoscopy examination between 2008 and 2019, yielding a diagnosis of CRC were identified from medical records. The subjects were classified into two groups according to their age at diagnosis, namely early-onset (18-49 years old) and late-onset (≥ 50-years-old). Demographic data, characteristics, and risk factors of both onset age groups were evaluated using the chi-square and Fisher's exact test. RESULTS Among 495 CRC patients confirmed by histopathology, 205 (41.4%) were classified as early-onset and 290 (58.6%) as late-onset. Most subjects in the early-onset CRC group were male (53.7%), with 89.8% displaying adenocarcinoma histopathology. A majority (78%) of the early-onset CRC patients had left-sided tumors, with the rectum (41%) and rectosigmoid (17.6%) being the most common sites. Abdominal pain was the most frequent symptom in the early-onset CRC patients (55.6%), which was significantly higher than that in the late-onset CRC patients (43.8%, P < 0.05). Early-onset CRC cases were more likely to be underweight (34.6% vs 20.0%, P < 0.001) compared to late-onset CRC cases. The proportion of subjects with suspected hereditary nonpolyposis colorectal cancer (HNPCC) was also higher in the early-onset CRC group than in the late-onset age group (9.3% vs 4.1%, P < 0.05). However, no difference was observed in the parental or family histories of CRC cases. CONCLUSION Early-onset CRC patients were more likely to have abdominal pain, underweight status, and HNPCC suspicion than late-onset CRC patients.
Collapse
Affiliation(s)
- Dadang Makmun
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Marcellus Simadibrata
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Murdani Abdullah
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Ari F Syam
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Hamzah Shatri
- Clinical Epidemiology Unit, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Achmad Fauzi
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Kaka Renaldi
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Hasan Maulahela
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Amanda P Utari
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Rabbinu R Pribadi
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Virly N Muzellina
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Saskia A Nursyirwan
- Division of Gastroenterology, Pancreatobiliary & Digestive Endoscopy, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| |
Collapse
|
|
24
|
Spot-light on microbiota in obesity and cancer. Int J Obes (Lond) 2021; 45:2291-2299. [PMID: 34363002 DOI: 10.1038/s41366-021-00866-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 03/26/2021] [Accepted: 05/18/2021] [Indexed: 02/06/2023]
Abstract
Over the last few years, the complexity and diversity of gut microbiota within and across individuals has been detailed in relation to human health. Further, understanding of the bidirectional association between gut microbiota and metabolic disorders has highlighted a complimentary, yet crucial role for microbiota in the onset and progression of obesity-related cancers. While strategies for cancer prevention and cure are known to work efficiently when supported by healthy diet and lifestyle choices and physical activity, emerging evidence suggests that the complex interplay relating microbiota both to neoplastic and metabolic diseases could aid strategies for cancer treatment and outcomes. This review will explore the experimental and clinical grounds supporting the functional role of gut microbiota in the pathophysiology and progression of cancers in relation to obesity and its metabolic correlates. Therapeutic approaches aiding microbiota restoration in connection with cancer treatments will be discussed.
Collapse
|
|
25
|
Li H, Boakye D, Chen X, Hoffmeister M, Brenner H. Association of Body Mass Index With Risk of Early-Onset Colorectal Cancer: Systematic Review and Meta-Analysis. Am J Gastroenterol 2021; 116:2173-2183. [PMID: 34309586 PMCID: PMC8560162 DOI: 10.14309/ajg.0000000000001393] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 06/10/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Incidence of colorectal cancer (CRC) in young adults has been increasing in recent decades in many countries for still widely unclear reasons. Suspected candidates include increasing prevalence of overweight and obesity, but specific evidence on their role for early-onset CRC (EOCRC) is sparse. We conducted a systematic review and meta-analysis to summarize available evidence on the association of body mass index (BMI) with EOCRC. METHODS We systematically searched PubMed, EMBASE, and Web of Science up to February 2021 for studies that evaluated the association of BMI (before diagnosis but not near diagnosis) with CRC risk and reported specific results for EOCRC. Results from studies with similar BMI groupings were summarized in meta-analyses using random-effects models. RESULTS Twelve studies were eligible and included. Results of 6 studies were pooled in meta-analyses, which yielded a higher risk of EOCRC for overweight and obesity (BMI ≥25 kg/m2) compared with normal weight (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.19-1.68). An increasing risk with increasing BMI was observed, with much higher risk for obesity (OR 1.88, 95% CI 1.40-2.54) than for overweight (OR 1.32, 95% CI 1.19-1.47). DISCUSSION Obesity is a strong risk factor for EOCRC, and its increasing prevalence in younger generations is likely to substantially contribute to the increase in EOCRC. Efforts to limit the obesity epidemic in adolescents and younger adults may be crucial for reducing CRC incidence in future generations of adults.
Collapse
Affiliation(s)
- Hengjing Li
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Daniel Boakye
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Xuechen Chen
- 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
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
Collapse
|
|
26
|
Schumacher AJ, Chen Q, Attaluri V, McLemore EC, Chao CR. Metabolic Risk Factors Associated with Early-Onset Colorectal Adenocarcinoma: A Case-Control Study at Kaiser Permanente Southern California. Cancer Epidemiol Biomarkers Prev 2021; 30:1792-1798. [PMID: 34301728 DOI: 10.1158/1055-9965.epi-20-1127] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 02/22/2021] [Accepted: 07/07/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The incidence of early-onset colorectal cancer (eoCRC) diagnosed among individuals under age 50 has been rising. However, risk factors for eoCRC are unclear. We investigated whether metabolic abnormalities are risk factors for eoCRC adenocarcinoma. METHODS Invasive colorectal adenocarcinoma cases diagnosed between ages 15 and 49 from 2008 to 2018 at Kaiser Permanente Southern California (KPSC) were identified. Those with a history of inflammatory bowel disease were excluded. Noncancer controls were selected 5:1 for each case matched by age, sex, and length of membership prior to index date. Data were collected from KSPC's electronic medical records. The exposures of interest included obesity, type II diabetes, hypertension, and dyslipidemia, assessed from ≥1 year prior to eoCRC diagnosis/index date. Conditional logistic regressions were used to evaluate the associations between these metabolic risk factors and risk of eoCRC adenocarcinoma, adjusting for race/ethnicity, smoking, family history, neighborhood socioeconomic status, and health care utilization. RESULTS A total of 1,032 cases and 5,128 controls were included. Risk of colorectal adenocarcinoma was significantly associated with obesity [odds ratio (OR) = 1.41; 95% confidence interval (CI), 1.15-1.74], but not diabetes, hypertension or dyslipidemia. In analysis stratified by tumor location, obesity was significantly associated with risk of colon adenocarcinoma OR = 1.56 (1.17-2.07), but its association with rectal adenocarcinoma was less clear OR = 1.19 (0.85-1.68). No significant interaction was detected between obesity and age (≥40 vs. <40), and obesity and sex. CONCLUSIONS Obesity was associated with risk for eoCRC adenocarcinoma. IMPACT This finding could help inform early-onset colorectal adenocarcinoma screening and prevention recommendations.See related commentary by Hayes, p. xxx.
Collapse
Affiliation(s)
- Andrew J Schumacher
- Department of Radiation Oncology, Torrance Memorial Medical Center, Torrance, California
| | - Qiaoling Chen
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
| | - Vikram Attaluri
- Department of General Surgery, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
| | - Elisabeth C McLemore
- Department of General Surgery, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
| | - Chun R Chao
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California.
| |
Collapse
|
|
27
|
Reddy S, Mouchli A, Bierle L, Gerrard M, Walsh C, Mir A, Lebel DP, Mason C, Grider D, Rubio M. Assessing Presenting Symptoms, Co-Morbidities, and Risk Factors for Mortality in Underserved Patients With Non-Hereditary Early-Onset Colorectal Cancer. Cureus 2021; 13:e16117. [PMID: 34350080 PMCID: PMC8325966 DOI: 10.7759/cureus.16117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2021] [Indexed: 12/27/2022] Open
Abstract
Background The presenting symptoms and co-morbidities contributing to mortality in young patients (age < 50 years old) with colorectal cancer (CRC) are poorly understood. We reviewed these features in our patient population with non-hereditary early-onset CRC (EO-CRC). Study aim This study aimed to assess characteristics of patients with a diagnosis of non-hereditary EO-CRC, including presenting symptoms and metabolic disorders contributing to mortality in underserved areas of southwest Virginia. Methods In this retrospective observational study, we selected patients aged 18-50 years with a diagnosis of non-hereditary EO-CRC from 2008 to 2016 at Carilion Roanoke Memorial Hospital. The electronic medical record was queried to identify demographic data, medical history, histopathology results, lab values, and mortality. The cumulative risks of symptoms and co-morbid metabolic disorders was estimated using Kaplan-Meier curves. Results We identified 139 patients with non-hereditary EO-CRC (mean age 41.6 ± 6.9 years). Almost half of these patients were obese (BMI > 30), 30.9% had a diagnosis of hypertension, 29% had hyperlipidemia (HLD), and 17.35% had diabetes mellitus type 2 (DM2). Diagnosis was delayed by 4.5 months from initial presentation, and 17% had advanced disease (stage III/IV). Also, 68.5% of patients were symptomatic with one to three symptoms, most commonly with rectal bleeding (45.3%). The chronicity of HLD (≥5 years) was associated with reduced survival in our patients with EO-CRC. The survival of females with multiple metabolic disorders was reduced compared to females with a single metabolic disorder. Conclusions Multiple symptoms, chronic HLD, and female gender with multiple metabolic disorders were factors associated with poor outcomes in non-hereditary EO-CRC patients.
Collapse
Affiliation(s)
| | - Awf Mouchli
- Gastroenterology, Cleveland Clinic, Cleveland, USA
| | | | - Miranda Gerrard
- Medical Student, Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, USA
| | | | - Adil Mir
- Internal Medicine, Carilion Clinic, Roanoke, USA
| | - David P Lebel
- Pathology, Virginia Tech Carilion School of Medicine, Roanoke, USA
| | | | - Douglas Grider
- Pathology, Carilion Roanoke Memorial Hospital, Roanoke, USA
- Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, USA
| | - Marrieth Rubio
- Gastroenterology and Hepatology, Virginia Tech Carilion School of Medicine, Roanoke, USA
| |
Collapse
|
|
28
|
Ku MS, Chiu SYH, Chien KL, Lee YC, Chen SLS, Chen CD. Gender difference in metabolic syndrome and incident colorectal adenoma: A prospective observational study (KCIS No.42). Medicine (Baltimore) 2021; 100:e26121. [PMID: 34087861 PMCID: PMC8183717 DOI: 10.1097/md.0000000000026121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 04/18/2021] [Accepted: 05/10/2021] [Indexed: 01/04/2023] Open
Abstract
ABSTRACT This community-based study aimed to elucidate whether there is a gender difference in the effect of metabolic syndrome (MetS) and its individual components on an elevated risk for incident colorectal adenoma.A prospective cohort study was conducted by enrolling 59,767 subjects aged 40 years or older between 2001 and 2009 in Keelung, Taiwan, to test this hypothesis, excluding those with a prior history of colorectal cancer and those with colorectal cancer diagnosed at the first screening. Cox proportional hazards regression models were used to assess the effect of MetS in terms of a dichotomous classification, each individual component and the number of components for males and females.Colorectal adenoma was present in 2.7% (n = 652) of male participants and 1.1% (n = 403) of female participants. The prevalence rate of MetS was 26.7% and 23.3% for males and females, respectively. The effect of MetS on colorectal adenoma was statistically significant and similar for the 2 genders, with an adjusted hazard ratio (aHR) of 1.33 (95% CI: 1.13-1.58) in males and 1.33 (95% CI: 1.06-1.66) in females after adjustment for confounders. However, MetS led to higher risk of advanced colorectal adenoma in men than in women. Regarding the effect of each component of MetS on colorectal adenoma, abnormal waist circumference and hypertriglyceridemia led to an elevated risk of colorectal adenoma in both genders. A rising risk of colorectal adenoma among females was noted in those with a moderately higher level of glycemia (100-125 mg/dL, aHR = 1.44, 95% CI: 1.12-1.85). Hypertriglyceridemia and high blood pressure were associated with an increased risk of advance colorectal adenoma in males.Both male and female subjects with MetS had a higher risk of colorectal adenoma. The contributions from individual components of MetS varied by gender. These findings suggest that the possible risk reduction of colorectal adenoma through metabolic syndrome-based lifestyle modifications may differ between genders.
Collapse
Affiliation(s)
- Mei-Sheng Ku
- Institute of Environmental and Occupational Health Science, College of Public Health, National Taiwan University, Taipei
| | - Sherry Yueh-Hsia Chiu
- Department of Health Care Management, College of Management, Chang Gung University, Taoyuan
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung
| | - Kuo-Liong Chien
- Institute of Epidemiology and Preventive Medicine, College of Public School
- Department of Internal Medicine, College of Medicine
- Innovation and Policy Center for Population Health and Sustainable Environment, College of Public Health, National Taiwan University
| | - Yi-Chia Lee
- Institute of Epidemiology and Preventive Medicine, College of Public School
- Department of Internal Medicine, College of Medicine
- Innovation and Policy Center for Population Health and Sustainable Environment, College of Public Health, National Taiwan University
- Department of Medical Research, National Taiwan University Hospital
| | - Sam Li-Sheng Chen
- School of Oral Hygiene, College of Oral Medicine
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei
| | - Chih-Dao Chen
- Department of Family Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| |
Collapse
|
|
29
|
Dairi O, Anderson JC, Butterly LF. Why is colorectal cancer increasing in younger age groups in the United States? Expert Rev Gastroenterol Hepatol 2021; 15:623-632. [PMID: 33480301 DOI: 10.1080/17474124.2021.1876561] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: While colorectal cancer (CRC) incidence and mortality have decreased for older adults, the rates are increasing in adults younger than 50 years of age in the United States as well as globally. In response to strong epidemiologic evidence as well as sophisticated models, the American Cancer Society (ACS) has recommended screening adults for CRC starting at age 45. Understanding the factors associated with the rise of incidence in adults younger than age 50 may help to identify those adults who may be at greatest risk.Areas covered: In this review, we provide an overview of the recent literature and discuss possible explanations for the increase in CRC in young adults including obesity and other recognized CRC risk factors, delay in diagnosis of symptomatic patients (<50 years of age), and review perspectives on the current and future status of the field.Expert opinion: Currently there are little data regarding risk factors for CRC in average risk young adults who are asymptomatic. With potential endorsement of screening at 45 years of age by US Preventive Services Task Force, more data regarding clinical and molecular risk factors associated with CRC in young adults will be available.
Collapse
Affiliation(s)
- Obaida Dairi
- Department of Veterans Affairs Medical Center, White River Junction, VT and the Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Joseph C Anderson
- Department of Veterans Affairs Medical Center, White River Junction, VT and the Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,Division of Gastroenterology and Hepatology, University of Connecticut School of Medicine, Farmington, CT, USA.,New Hampshire Colonoscopy Registry, Lebanon, NH, USA
| | - Lynn F Butterly
- New Hampshire Colonoscopy Registry, Lebanon, NH, USA.,Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| |
Collapse
|
|
30
|
Behavioral Risk Factors and Risk of Early-Onset Colorectal Cancer: Review of the Mechanistic and Observational Evidence. CURRENT COLORECTAL CANCER REPORTS 2021. [DOI: 10.1007/s11888-021-00465-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|