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Shirzad S, Eterafi M, Karimi Z, Barazesh M. MicroRNAs involved in colorectal cancer, a rapid mini-systematic review. BMC Cancer 2025; 25:934. [PMID: 40413456 DOI: 10.1186/s12885-025-14343-1] [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: 11/29/2024] [Accepted: 05/16/2025] [Indexed: 05/27/2025] Open
Abstract
INTRODUCTION Colorectal cancer (CRC) involves the uncontrolled proliferation of glandular epithelial cells in the colon or rectum. The high mortality rate associated with CRC has driven extensive research into innovative diagnostic and therapeutic strategies. Among these, microRNAs (miRNA) have gained attention for their crucial role in regulating various cellular processes that contribute to the initiation, progression, and metastasis of CRC. METHOD This systematic review aimed to assess the roles of various miRNAs in CRC by analyzing multiple studies. The PICO framework was followed to structure the study regarding miRNA involved in CRC development and progression compared to normal cases. The outcomes were measured according miRNAs impact on CRC progression, survival rates, and treatment response. Systematic review of studies published from 2000 to November 2023 were included. Data were collected from prominent databases, including Google Scholar, PubMed, ScienceDirect, Irandoc, SID, and Magiran, covering studies from 2000 to November 2023. Studies were managed using EndNote for citation management, and duplicates were removed. The remaining studies were evaluated based on predefined inclusion and exclusion criteria. RESULTS In our review, we categorized 28 miRNAs based on their potential tumor suppressor or oncogenic effects in CRC progression. Among them, 14 miRNAs were highlighted as important based on the assessment using TCGA data, with miR-200a also showing a significant effect on patient survival. CONCLUSION This study compiled and analyzed validated miRNAs associated with CRC progression. The findings suggest the potential of these miRNAs as non-invasive biomarkers, which may be used alone or in combination with traditional tumor markers for improved diagnostic and prognostic applications in CRC. This review contributes novel insights by updating the current understanding and offering a comprehensive evaluation of miRNAs in CRC.
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Affiliation(s)
- Sogol Shirzad
- Students Research Committee, Gerash University of Medical Sciences, Gerash, Iran
- Medical Biotechnology Group, Gerash University of Medical Sciences, Gerash, Iran
| | - Majid Eterafi
- Students Research Committee, Gerash University of Medical Sciences, Gerash, Iran
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Zeinab Karimi
- Medical Biotechnology Group, Gerash University of Medical Sciences, Gerash, Iran.
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran.
| | - Mahdi Barazesh
- Medical Biotechnology Group, Gerash University of Medical Sciences, Gerash, Iran
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
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Zhao J, Ji H, Li K, Yu G, Zhou S, Xiao Q, Dunlop M, Theodoratou E, Li X, Ding K. Decoding the genetic and environmental forces in propelling the surge of early-onset colorectal cancer. Chin Med J (Engl) 2025; 138:1163-1174. [PMID: 40251115 PMCID: PMC12091620 DOI: 10.1097/cm9.0000000000003601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Indexed: 04/20/2025] Open
Abstract
ABSTRACT Early-onset colorectal cancer (EOCRC) shows a different epidemiological trend compared to later-onset colorectal cancer, with its incidence rising in most regions and countries worldwide. However, the reasons behind this trend remain unclear. The etiology of EOCRC is complex and could involve both genetic and environmental factors. Apart from Lynch syndrome and Familial Adenomatous Polyposis, sporadic EOCRC exhibits a broad spectrum of pathogenic germline mutations, genetic polymorphisms, methylation changes, and chromosomal instability. Early-life exposures and environmental risk factors, including lifestyle and dietary risk factors, have been found to be associated with EOCRC risk. Meanwhile, specific chronic diseases, such as inflammatory bowel disease, diabetes, and metabolic syndrome, have been associated with EOCRC. Interactions between genetic and environmental risk factors in EOCRC have also been explored. Here we present findings from a narrative review of epidemiological studies on the assessment of early-life exposures, of EOCRC-specific environmental factors, and their interactions with susceptible loci. We also present results from EOCRC-specific genome-wide association studies that could be used to perform Mendelian randomization analyses to ascertain potential causal links between environmental factors and EOCRC.
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Affiliation(s)
- Jianhui Zhao
- School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310009, China
| | - Haosen Ji
- School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Kangning Li
- School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Guirong Yu
- School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Siyun Zhou
- School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Qian Xiao
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310009, China
| | - Malcolm Dunlop
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh EH8 9DX, United Kingdom
- Colon Cancer Genetics Group, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh EH8 9DX, United Kingdom
- Colon Cancer Genetics Group, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom
| | - Xue Li
- School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310009, China
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310009, China
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310009, China
- Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China
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Pretzsch E, Peschel CA, Rokavec M, Torlot L, Li P, Hermeking H, Werner J, Klauschen F, Neumann J, Jung A, Kumbrink J. Five-Gene Expression Signature Associated With Acquired FOLFIRI Resistance and Survival in Metastatic Colorectal Cancer. J Transl Med 2025; 105:104107. [PMID: 39954853 DOI: 10.1016/j.labinv.2025.104107] [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: 08/15/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 02/17/2025] Open
Abstract
FOLFIRI, a combination of folinic acid, 5-fluorouracil, and irinotecan, is one of the recommended first-line chemotherapeutic treatments for metastatic colorectal cancer. Unfortunately, acquired FOLFIRI resistance represents a common obstacle in the treatment of metastatic colorectal cancer patients. Thus, we aimed to identify mechanisms, gene alterations, and gene expression signatures contributing to acquired FOLFIRI resistance by mimicking this problem in a cell culture model and subsequent translation in clinical data sets. Three FOLFIRI-resistant colorectal cancer (CRC) cell lines were established by continuous FOLFIRI treatment. Comparative mutation screening (161 genes) and transcriptomics (pathway and differential expression analyses) were performed in parental and resistant cells. Data reconciliation was performed in GSE62322, a clinical FOLFIRI responder data set (intrinsic resistance). Relapse-free survival (RFS) associations of identified differentially expressed genes and potential gene signatures were investigated in 8 clinical CRC data sets. No mutual genetic alterations were found in FOLFIRI-resistant derivatives. Resistant cell lines displayed activation of mitogen-activated protein kinase, immune response, and epithelial-mesenchymal transition pathways. Twelve differentially expressed genes, significantly differentially expressed in at least 2 of the 3 resistant cell lines, were identified. Comparison with GSE62322 and subsequent survival analyses revealed a 5-gene FOLFIRI signature comprised of CAV2, TNC, TACSTD2, SERPINE2, and PERP that was associated with RFS in multiple data sets including the cancer genome atlas CRC (hazard ratio [HR] =2.634, P = 4.53 × 10-6), in pooled samples of all data sets (all stages [N = 1981]: HR = 1.852, P = 6.44 × 10-13; stage IV [N = 260]: HR = 2.462, P = 5.22 × 10-9). A multivariate Cox regression analysis identified the 5-gene signature as an independent prognostic factor in the cancer genome atlas data set (HR = 1.89, P = .0202). Our analyses revealed a 5-gene FOLFIRI resistance signature associated with RFS that may help predict FOLFIRI resistance and thus avoid unnecessary ineffective treatment. Signature members might also represent targets to fight FOLFIRI resistance.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Christiane A Peschel
- Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Lucien Torlot
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Germany
| | - Pan Li
- Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Heiko Hermeking
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Experimental and Molecular Pathology, Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Frederick Klauschen
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Neumann
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Andreas Jung
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jörg Kumbrink
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany.
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Cohen D, Rogers C, Gabre J, Dionigi B. The Young: Early-Onset Colon Cancer. Clin Colon Rectal Surg 2025; 38:173-178. [PMID: 40292000 PMCID: PMC12020630 DOI: 10.1055/s-0044-1787883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Early-onset colorectal cancer (EO-CRC), characterized by diagnosis before the age of 50 years, has emerged as a significant healthcare challenge with increasing global incidence. While traditional risk factors such as family history and inherited syndromes contribute to EO-CRC, a substantial proportion of cases remain sporadic, necessitating further investigation into additional etiological factors. Molecular studies reveal heterogeneity in EO-CRC, with distinct mutational profiles compared to late-onset CRC. Clinical management presents unique considerations, including challenges in early detection and treatment strategies tailored to younger patients. Addressing EO-CRC requires a multidisciplinary approach integrating epidemiological, molecular, and clinical insights to improve prevention, diagnosis, and therapeutic outcomes. Emerging research avenues explore novel biomarkers and therapeutic targets, offering promise for advancing understanding and management of this disease in contemporary oncology practice.
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Affiliation(s)
- David Cohen
- Department of Surgery, New York-Presbyterian/Columbia University Irving Medical Center, New York, New York
| | - Caitlin Rogers
- Herbert Irving Comprehensive Cancer Research Center, Columbia University, New York, New York
| | - Joel Gabre
- Herbert Irving Comprehensive Cancer Research Center, Columbia University, New York, New York
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Beatrice Dionigi
- Division of Colon and Rectal Surgery, New York-Presbyterian/Columbia University Medical Center, New York, New York
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Li W, Liu J, Lan Y, Yu D, Zhang B. Development and validation of survival prediction tools in early and late onset colorectal cancer patients. Sci Rep 2025; 15:12864. [PMID: 40229310 PMCID: PMC11997042 DOI: 10.1038/s41598-025-95385-0] [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: 09/01/2024] [Accepted: 03/20/2025] [Indexed: 04/16/2025] Open
Abstract
This study aims to develop online calculators using machine learning models to predict survival probabilities for early- and late-onset colorectal cancer (EOCRC and LOCRC) over a 1- to 8-year period. We extracted data on 117,965 CRC patients from the published database spanning 2010 to 2021, divided into training and internal testing datasets. The data of 200 CRC patients from Chongqing Hospital of Jiangsu Province Hospital was used as the external testing dataset. We conducted univariate and multivariate regression analyses on the training dataset to identify key survival factors and develop predictive machine learning models. The models were evaluated using internal and external testing datasets based on AUC, accuracy, precision, recall, and F1 score. Web-based calculators were subsequently developed to predict survival curves for EOCRC and LOCRC patients under different treatment strategies. In the multivariate Cox regression analysis, 16 and 18 variables were independently significant survival factors for EOCRC and LOCRC, respectively. In the EOCRC group, the machine learning models achieved AUC values of 0.880 and 0.804 in the internal and external testing cohorts. For the LOCRC group, the machine learning models exhibited AUC values of 0.857 and 0.823 in the internal and external testing cohorts. The online calculators, powered by trained machine learning models, are accessible at https://eocrc-surv.streamlit.app/ and https://locrc-surv.streamlit.app/ . These tools estimate survival probabilities for EOCRC and LOCRC patients under various treatment strategies and display the corresponding survival curves post-treatment over the 1- to 8-year period. This study successfully developed online calculators using machine learning algorithms to predict 1- to 8-year survival probabilities for EOCRC and LOCRC patients under various treatment strategies.
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Affiliation(s)
- Wanling Li
- Department of Gastroenterology, University-Town Hospital of Chongqing Medical University, Chongqing, 401331, China
- Department of Gastroenterology, Chongqing Hospital of Jiangsu Province Hospital, The People's Hospital of Qijiang District, Chongqing, 401420, China
| | - Jinshan Liu
- Department of Gastrointestinal Surgery, Chongqing Hospital of Jiangsu Province Hospital, The People's Hospital of Qijiang District, Chongqing, 401420, China
| | - Yuntong Lan
- Department of Gastroenterology, Chongqing Hospital of Jiangsu Province Hospital, The People's Hospital of Qijiang District, Chongqing, 401420, China
| | - Dongling Yu
- Department of Gastrointestinal Surgery, Chongqing Hospital of Jiangsu Province Hospital, The People's Hospital of Qijiang District, Chongqing, 401420, China
| | - Bingqiang Zhang
- Department of Gastroenterology, University-Town Hospital of Chongqing Medical University, Chongqing, 401331, China.
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Yildirim HC, Gunenc D, Almuradova E, Sutcuoglu O, Yalcin S. A Narrative Review of RAS Mutations in Early-Stage Colorectal Cancer: Mechanisms and Clinical Implications. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:408. [PMID: 40142219 PMCID: PMC11944112 DOI: 10.3390/medicina61030408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/19/2025] [Accepted: 02/22/2025] [Indexed: 03/28/2025]
Abstract
Colorectal cancer (CRC) is the third-most common cancer globally and a leading cause of cancer-related deaths. While the prognostic and predictive roles of RAS mutations in advanced CRC are well-established, their significance in early-stage CRC remains a topic of debate. Studies have been conducted for many years on clinical and pathological parameters that may be associated with RAS mutation, and there are inconsistent results in this regard. Currently, the only biomarker used in early-stage CRC is microsatellite status. KRAS mutations are detected in 40-50% of patients with colorectal cancer. RAS activating mutations cause loss of EGFR regulation by acting on the RAS/RAF/MAPK signaling pathways. In advanced colorectal cancer, these mechanisms cause a decrease in the effectiveness of EGFR inhibitors. However, studies on patients with early-stage colorectal cancer have inconsistent results. This review highlights the prognostic and clinical significance of KRAS mutations in early-stage CRC, particularly in MSS tumors. In the MSS group, KRAS mutations were associated with shorter TTR and OS compared to DWT patients. In contrast, in the MSI-H group, KRAS mutations showed no prognostic effect in TTR and OS. However. KRAS mutations were associated with shorter SAR in both MSI-H and MSS groups of patients. The findings underscore the need for routine molecular profiling, including KRAS and MSI status, to refine risk stratification and guide adjuvant therapy decisions. Further studies are warranted to explore targeted therapeutic approaches for KRAS-mutant CRC in the adjuvant setting.
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Affiliation(s)
- Hasan Cagri Yildirim
- Department of Medical Oncology, Nigde Training and Research Hospital, 51100 Nigde, Turkey
| | - Damla Gunenc
- Department of Medical Oncology, Ege University Faculty of Medicine, 35040 Izmir, Turkey;
| | | | - Osman Sutcuoglu
- Department of Medical Oncology, Etlik City Hospital, 06170 Ankara, Turkey;
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey;
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Moiz S, Saha B, Mondal V, Bishnu D, Das B, Bose B, Das S, Banerjee N, Dutta A, Chatterjee K, Goswami S, Mukhopadhyay S, Basu S. Differential Expression of miRNAs Between Young-Onset and Late-Onset Indian Colorectal Carcinoma Patients. Noncoding RNA 2025; 11:10. [PMID: 39997610 PMCID: PMC11858122 DOI: 10.3390/ncrna11010010] [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: 11/07/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 02/26/2025] Open
Abstract
Reports indicate a worldwide increase in the incidence of Early-Onset Colorectal Carcinoma (EOCRC) (<50 years old). In an effort to understand the different modes of pathogenesis in early-onset CRC, colorectal tumors from EOCRC (<50 years old) and Late-Onset patients (LOCRC; >50 years old) were screened to eliminate microsatellite instability (MSI), nuclear β-catenin, and APC mutations, as these are known canonical factors in CRC pathogenesis. Small-RNA sequencing followed by comparative analysis revealed differential expression of 23 miRNAs (microRNAs) specific to EOCRC and 11 miRNAs specific to LOCRC. We validated the top 10 EOCRC DEMs in TCGA-COAD and TCGA-READ cohorts, followed by validation in additional EOCRC and LOCRC cohorts. Our integrated analysis revealed upregulation of hsa-miR-1247-3p and hsa-miR-148a-3p and downregulation of hsa-miR-326 between the two subsets. Experimentally validated targets of the above miRNAs were compared with differentially expressed genes in the TCGA dataset to identify targets with physiological significance in EOCRC development. Our analysis revealed metabolic reprogramming, downregulation of anoikis-regulating pathways, and changes in tissue morphogenesis, potentially leading to anchorage-independent growth and progression of epithelial-mesenchymal transition (EMT). Upregulated targets include proteins present in the basal part of intestinal epithelial cells and genes whose expression is known to correlate with invasion and poor prognosis.
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Affiliation(s)
- Sumaiya Moiz
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
| | - Barsha Saha
- Biotechnology Research and Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani 741251, India; (B.S.); (S.G.)
- Regional Centre for Biotechnology, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad 121001, India
| | - Varsha Mondal
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA
| | - Debarati Bishnu
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
| | - Biswajit Das
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
| | - Bodhisattva Bose
- Department of Surgical Oncology, All India Institute of Medical Sciences (AIIMS), Rishikesh 249203, India;
- Department of General Surgery, Nil Ratan Sircar Medical College and Hospital, Kolkata 700014, India
| | - Soumen Das
- Department of Surgical Oncology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India;
| | - Nirmalya Banerjee
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
- Department of Histopathology, Narayana Superspeciality Hospital, Kolkata 700099, India
| | - Amitava Dutta
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
| | - Krishti Chatterjee
- Department of Histopathology, Netaji Subhas Chandra Bose Cancer Hospital, Kolkata 700094, India; (B.D.); (N.B.); (A.D.); (K.C.)
- Department of Pathology, Neotia Bhagirathi Woman and Child Care Centre, Kolkata 700017, India
| | - Srikanta Goswami
- Biotechnology Research and Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani 741251, India; (B.S.); (S.G.)
- Regional Centre for Biotechnology, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad 121001, India
| | - Soma Mukhopadhyay
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
| | - Sudarshana Basu
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India; (S.M.); (V.M.); (D.B.)
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Alshenaifi JY, Vetere G, Maddalena G, Yousef M, White MG, Shen JP, Vilar E, Parseghian C, Dasari A, Morris VK, Huey R, Overman MJ, Wolff R, Raghav KP, Willis J, Alfaro K, Futreal A, You YN, Kopetz S. Mutational and co-mutational landscape of early onset colorectal cancer. Biomarkers 2025; 30:64-76. [PMID: 39761813 PMCID: PMC11856746 DOI: 10.1080/1354750x.2024.2447089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025]
Abstract
INTRODUCTION Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades. METHODS Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, < 50 years) compared to late-onset (LOCRC, ≥ 50 years). RESULTS EOCRC was associated with a higher prevalence of Asian and Hispanic patients, rectal or left-sided tumors (72% vs. 59%), and advanced-stage disease. Molecular analyses revealed differences in mutation patterns, with EOCRC having higher frequencies of TP53 (74% vs. 68%, p < 0.01) and SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p < 0.001) and NOTCH1 (2.7% vs. 4.1%, p = 0.01) mutations were more prevalent in LOCRC. Stratification by tumor site and MSI status highlighted significant location- and age-specific molecular differences, such as increased KRAS and CTNNB1 mutations in right-sided EOCRC and higher BRAF prevalence in MSI-H LOCRC (47% vs. 6.7%, p < 0.001). Additionally, co-occurrence analysis revealed unique mutational networks in EOCRC MSS, including significant co-occurrences of FBXW7 with NOTCH3, RB1, and PIK3R1. CONCLUSION This study highlights the significance of age-specific molecular profiling, offering insights into the unique biology of EOCRC and potential clinical applications.
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Affiliation(s)
- Jumanah Yousef Alshenaifi
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Guglielmo Vetere
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Giulia Maddalena
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mahmoud Yousef
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael G. White
- Department of Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - John Paul Shen
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Eduardo Vilar
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Christine Parseghian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Van Karlyle Morris
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ryan Huey
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael J. Overman
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert Wolff
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kanwal P. Raghav
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jason Willis
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kristin Alfaro
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Andy Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Y. Nancy You
- Department of Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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9
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Pretta A, Ziranu P, Perissinotto E, Ghelardi F, Marmorino F, Giampieri R, Puci M, De Grandis MC, Lai E, Nasca V, Ciraci P, Puzzoni M, Cerma K, Sciortino C, Taravella A, Pretta G, Giuliani L, Damonte C, Pusceddu V, Sotgiu G, Berardi R, Lonardi S, Bergamo F, Pietrantonio F, Cremolini C, Scartozzi M. Early onset metastatic colorectal cancer patients as a distinctive clinical and molecular phenomenon. Br J Cancer 2025; 132:188-194. [PMID: 39604610 PMCID: PMC11756416 DOI: 10.1038/s41416-024-02902-5] [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: 08/31/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Despite a reduction of both incidence and mortality from CRC, recent studies have shown an increase in the incidence of early-onset CRC (EO-CRC). Data on this setting are limited. The aim of our study was to evaluate the clinical and molecular profiles of metastatic EO-CRC patients in order to identify differences compared to a late-onset CRC (LO-CRC) control group. METHODS We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions. The main objective was to the evaluate clinical outcome for EO-CRC patients in comparison to patients included in the control group. RESULTS In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p < 0,0001). In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo (p = 0,0156). In RAS/BRAF wild-type EO-CRC mOS was 43,0 vs 50,0 mo (p = 0,0290). mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p < 0,0001). CONCLUSION Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research.
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Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Eleonora Perissinotto
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Filippo Ghelardi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Marmorino
- Unit of Oncology, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research & New Technologies in Medicine & Surgery, University of Pisa, Pisa, Italy
| | - Riccardo Giampieri
- Clinica Oncologica - Dipartimento Scienze Cliniche e Molecolari - Università Politecnica delle Marche, Ancona, Italy
- Azienda Ospedaliero Universitaria delle Marche - Ancona, Ancona, Italy
| | - Mariangela Puci
- Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Sardinia, Italy
| | - Maria Caterina De Grandis
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Vincenzo Nasca
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Ciraci
- Unit of Oncology, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research & New Technologies in Medicine & Surgery, University of Pisa, Pisa, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Krisida Cerma
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Carolina Sciortino
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Ada Taravella
- Unit of Oncology, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research & New Technologies in Medicine & Surgery, University of Pisa, Pisa, Italy
| | - Gianluca Pretta
- Science department, King's School Hove, Hangleton, East Sussex, UK
| | - Lorenzo Giuliani
- Clinica Oncologica - Dipartimento Scienze Cliniche e Molecolari - Università Politecnica delle Marche, Ancona, Italy
- Azienda Ospedaliero Universitaria delle Marche - Ancona, Ancona, Italy
| | - Camilla Damonte
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giovanni Sotgiu
- Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Sardinia, Italy
| | - Rossana Berardi
- Clinica Oncologica - Dipartimento Scienze Cliniche e Molecolari - Università Politecnica delle Marche, Ancona, Italy
- Azienda Ospedaliero Universitaria delle Marche - Ancona, Ancona, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Francesca Bergamo
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Chiara Cremolini
- Unit of Oncology, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research & New Technologies in Medicine & Surgery, University of Pisa, Pisa, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
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10
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Li JS, Riggins K, Yang L, Chen C, Castro P, Alfarkh W, Zarrin-Khameh N, Scheurer ME, Creighton CJ, Musher B, Li W, Shen L. DNA methylation profiling at base-pair resolution reveals unique epigenetic features of early-onset colorectal cancer in underrepresented populations. Clin Epigenetics 2025; 17:11. [PMID: 39844333 PMCID: PMC11753045 DOI: 10.1186/s13148-025-01817-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 01/10/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND The incidence of early-onset colorectal cancer (EOCRC) has been rising at an alarming rate in the USA, and EOCRC disproportionately affects racial/ethnic minorities. Here, we construct comprehensive profiles of EOCRC DNA methylomes at base-pair resolution for a cohort of Hispanic and African American patients. RESULTS We show the epigenetic landscape of these EOCRC patients differs from that of late-onset colorectal cancer patients, and methylation canyons in EOCRC tumor tissue preferentially overlapped genes in cancer-related pathways. Furthermore, we identify epigenetic alterations in metabolic genes that are specific to our racial/ethnic minority EOCRC cohort but not Caucasian patients from TCGA. Top genes differentially methylated between these cohorts included the obesity-protective MFAP2 gene as well as cancer risk susceptibility genes APOL3 and RNASEL. CONCLUSIONS In this study, we provide to the scientific community high-resolution DNA methylomes for a cohort of EOCRC patients from underrepresented populations. Our exploratory findings in this cohort highlight epigenetic mechanisms underlying the pathogenesis of EOCRC and nominate novel biomarkers for EOCRC in underrepresented populations.
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Affiliation(s)
- Jason Sheng Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Karen Riggins
- Department of Medicine, Hematology and Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Li Yang
- Department of Pediatrics, USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chaorong Chen
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Patricia Castro
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Wedad Alfarkh
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Neda Zarrin-Khameh
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Pathology, Ben Taub Hospital, 1504 Taub Loop, Houston, TX, 77030, USA
| | - Michael E Scheurer
- Department of Pediatrics, Center for Epidemiology and Population Health, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chad J Creighton
- Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Benjamin Musher
- Department of Medicine, Gastrointestinal Medical Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Wei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA.
| | - Lanlan Shen
- Department of Pediatrics, USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA.
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11
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Zinkeng A, Taylor FL, Cheong SH, Song H, Merchant JL. Early Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence. Cell Mol Gastroenterol Hepatol 2024; 19:101425. [PMID: 39510499 PMCID: PMC11731505 DOI: 10.1016/j.jcmgh.2024.101425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/28/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early onset CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late-onset colorectal cancer development. To highlight this, we review the genetic and epigenetic modifications specific to early onset CRC. We also discuss the synergetic effect of single-nucleotide polymorphisms and environmental factors on the early onset of CRC. Additionally, we discuss the potential of noninvasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.
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Affiliation(s)
- Atehkeng Zinkeng
- Medical Scientist Training Program, University of Arizona College of Medicine, Tucson, Arizona
| | | | | | | | - Juanita L Merchant
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
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12
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Gan T, Wei X, Xing Y, Hu Z. Construction of Prognostic Prediction Models for Colorectal Cancer Based on Ferroptosis-Related Genes: A Multi-Dataset and Multi-Model Analysis. Biomed Eng Comput Biol 2024; 15:11795972241293516. [PMID: 39494419 PMCID: PMC11531666 DOI: 10.1177/11795972241293516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 10/07/2024] [Indexed: 11/05/2024] Open
Abstract
Background Colorectal cancer (CRC) remains a significant health burden globally, necessitating a deeper understanding of its molecular landscape and prognostic markers. This study characterized ferroptosis-related genes (FRGs) to construct models for predicting overall survival (OS) across various CRC datasets. Methods In TCGA-COAD dataset, differentially expressed genes (DEGs) were identified between tumor and normal tissues using DESeq2 package. Prognostic genes were identified associated with OS, disease-specific survival, and progression-free interval using survival package. Additionally, FRGs were downloaded from FerrDb website, categorized into unclassified, marker, and driver genes. Finally, multiple models (Coxboost, Elastic Net, Gradient Boosting Machine, LASSO Regression, Partial Least Squares Regression for Cox Regression, Ridge Regression, Random Survival Forest [RSF], stepwise Cox Regression, Supervised Principal Components analysis, and Support Vector Machines) were employed to predict OS across multiple datasets (TCGA-COAD, GSE103479, GSE106584, GSE17536, GSE17537, GSE29621, GSE39084, GSE39582, and GSE72970) using intersection genes across DEGs, OS, disease-specific survival, and progression-free interval, and FRG categories. Results Six intersection genes (ASNS, TIMP1, H19, CDKN2A, HOTAIR, and ASMTL-AS1) were identified, upregulated in tumor tissues, and associated with poor survival outcomes. In the TCGA-COAD dataset, the RSF model demonstrated the highest concordance index. Kaplan-Meier analysis revealed significantly lower OS probabilities in high-risk groups identified by the RSF model. The RSF model exhibited high accuracy with AUC values of 0.978, 0.985, and 0.965 for 1-, 3-, and 5-year survival predictions, respectively. Calibration curves demonstrated excellent agreement between predicted and observed survival probabilities. Decision curve analysis confirmed the clinical utility of the RSF model. Additionally, the model's performances were validated in GSE29621 dataset. Conclusions The study underscores the prognostic relevance of 6 intersection genes in CRC, providing insights into potential therapeutic targets and biomarkers for patient stratification. The RSF model demonstrates robust predictive performance, suggesting its utility in clinical risk assessment and personalized treatment strategies.
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Affiliation(s)
| | | | - Yuanhao Xing
- Department of Gastrointestinal Surgery, Liuzhou People’s Hospital affiliated to Guangxi Medical University, Liuzhou, Guangxi Province, China
| | - Zhili Hu
- Department of Gastrointestinal Surgery, Liuzhou People’s Hospital affiliated to Guangxi Medical University, Liuzhou, Guangxi Province, China
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13
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Lei JX, Wang R, Hu C, Lou X, Lv MY, Li C, Gai B, Wu XJ, Dou R, Cai D, Gao F. Deciphering tertiary lymphoid structure heterogeneity reveals prognostic signature and therapeutic potentials for colorectal cancer: a multicenter retrospective cohort study. Int J Surg 2024; 110:5627-5640. [PMID: 38833363 PMCID: PMC11392219 DOI: 10.1097/js9.0000000000001684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 05/10/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND Tertiary lymphoid structures (TLSs) exert a crucial role in the tumor microenvironment (TME), impacting tumor development, immune escape, and drug resistance. Nonetheless, the heterogeneity of TLSs in colorectal cancer (CRC) and their impact on prognosis and treatment response remain unclear. METHODS The authors collected genome, transcriptome, clinicopathological information, and digital pathology images from multiple sources. An unsupervised clustering algorithm was implemented to determine diverse TLS patterns in CRC based on the expression levels of 39 TLS signature genes (TSGs). Comprehensive explorations of heterogeneity encompassing mutation landscape, TME, biological characteristics, response to immunotherapy, and drug resistance were conducted using multiomics data. TLSscore was then developed to quantitatively assess TLS patterns of individuals for further clinical applicability. RESULTS Three distinct TLS patterns were identified in CRC. Cluster 1 exhibited upregulation of proliferation-related pathways, high metabolic activity, and intermediate prognosis, while Cluster 2 displayed activation of stromal and carcinogenic pathways and a worse prognosis. Both Cluster 1 and Cluster 2 may potentially benefit from adjuvant chemotherapy. Cluster 3, characterized by the activation of immune regulation and activation pathways, demonstrated a favorable prognosis and enhanced responsiveness to immunotherapy. The authors subsequently employed a regularization algorithm to construct the TLSscore based on nine core genes. Patients with lower TLSscore trended to prolonged prognosis and a more prominent presence of TLSs, which may benefit from immunotherapy. Conversely, those with higher TLSscore exhibited increased benefits from adjuvant chemotherapy. CONCLUSIONS The authors identified distinct TLS patterns in CRC and characterized their heterogeneity through multiomics analyses. The TLSscore held promise for guiding clinical decision-making and further advancing the field of personalized medicine in CRC.
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Affiliation(s)
- Jia-Xin Lei
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou Province
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, ShenzhenGuangdong Province
| | - Runxian Wang
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, ZhuhaiGuangdong Province
| | - Chuling Hu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou Province
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong Province
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou
| | - Xiaoying Lou
- Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou
| | - Min-Yi Lv
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou Province
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong Province
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou
| | - Chenghang Li
- Artificial Intelligence Thrust, The Hong Kong University of Science and Technology, Guangzhou, People's Republic of China
| | - Baowen Gai
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou Province
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong Province
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou
| | - Xiao-Jian Wu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou Province
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong Province
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou
| | - Ruoxu Dou
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, ZhuhaiGuangdong Province
| | - Du Cai
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou Province
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong Province
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou
| | - Feng Gao
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou Province
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong Province
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou
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14
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Tsumuraya H, Okayama H, Katagata M, Matsuishi A, Fukai S, Ito M, Sakamoto W, Saito M, Momma T, Nakajima S, Mimura K, Kono K. TGFβ-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis. Int J Mol Sci 2024; 25:4626. [PMID: 38731846 PMCID: PMC11083568 DOI: 10.3390/ijms25094626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 04/22/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Activated TGFβ signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFβ-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFβ-responsive, stroma-specific genes to infer TGFβ-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFβ-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFβ-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.
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Affiliation(s)
- Hideaki Tsumuraya
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Masanori Katagata
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Akira Matsuishi
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Satoshi Fukai
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Misato Ito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Wataru Sakamoto
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
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15
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Zhou Y, Chen X, Chen J, Kendrick CD, Ramanathan RK, Graham RP, Kossick KF, Boardman LA, Barrett MT. Genomic landscape of diploid and aneuploid microsatellite stable early onset colorectal cancer. Sci Rep 2024; 14:9368. [PMID: 38654044 DOI: 10.1038/s41598-024-59398-5] [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: 02/12/2024] [Accepted: 04/10/2024] [Indexed: 04/25/2024] Open
Abstract
Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have declined in recent decades. In contrast, there has been a steady increase in the incidence of CRC in individuals under 50 years of age. Hereditary syndromes contribute disproportionately to early onset CRC (EOCRC). These include microsatellite instability high (MSI+) tumors arising in patients with Lynch Syndrome. However, most EOCRCs are not associated with familial syndromes or MSI+ genotypes. Comprehensive genomic profiling has provided the basis of improved more personalized treatments for older CRC patients. However, less is known about the basis of sporadic EOCRC. To define the genomic landscape of EOCRC we used DNA content flow sorting to isolate diploid and aneuploid tumor fractions from 21 non-hereditary cases. We then generated whole exome mutational profiles for each case and whole genome copy number, telomere length, and EGFR immunohistochemistry (IHC) analyses on subsets of samples. These results discriminate the molecular features of diploid and aneuploid EOCRC and provide a basis for larger population-based studies and the development of effective strategies to monitor and treat this emerging disease.
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Affiliation(s)
- Yumei Zhou
- Department of Research, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | - Xianfeng Chen
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55905, USA
| | - Jun Chen
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55905, USA
| | - Conner D Kendrick
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Ramesh K Ramanathan
- Mayo Clinic Cancer Center, Phoenix, AZ, 85054, USA
- Ironwood Cancer and Research Center, Scottsdale, AZ, 85260, USA
| | | | - Kimberlee F Kossick
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Lisa A Boardman
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Michael T Barrett
- Department of Research, Mayo Clinic in Arizona, Scottsdale, AZ, USA.
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic in Arizona, Scottsdale, AZ, USA.
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16
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Qin Y, Tong X, Mei WJ, Cheng Y, Zou Y, Han K, Yu J, Jie Z, Zhang T, Zhu S, Jin X, Wang J, Yang H, Xu X, Zhong H, Xiao L, Ding PR. Consistent signatures in the human gut microbiome of old- and young-onset colorectal cancer. Nat Commun 2024; 15:3396. [PMID: 38649355 PMCID: PMC11035630 DOI: 10.1038/s41467-024-47523-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 04/03/2024] [Indexed: 04/25/2024] Open
Abstract
The incidence of young-onset colorectal cancer (yCRC) has been increasing in recent decades, but little is known about the gut microbiome of these patients. Most studies have focused on old-onset CRC (oCRC), and it remains unclear whether CRC signatures derived from old patients are valid in young patients. To address this, we assembled the largest yCRC gut metagenomes to date from two independent cohorts and found that the CRC microbiome had limited association with age across adulthood. Differential analysis revealed that well-known CRC-associated taxa, such as Clostridium symbiosum, Peptostreptococcus stomatis, Parvimonas micra and Hungatella hathewayi were significantly enriched (false discovery rate <0.05) in both old- and young-onset patients. Similar strain-level patterns of Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were observed for oCRC and yCRC. Almost all oCRC-associated metagenomic pathways had directionally concordant changes in young patients. Importantly, CRC-associated virulence factors (fadA, bft) were enriched in both oCRC and yCRC compared to their respective controls. Moreover, the microbiome-based classification model had similar predication accuracy for CRC status in old- and young-onset patients, underscoring the consistency of microbial signatures across different age groups.
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Affiliation(s)
- Youwen Qin
- BGI Research, Shenzhen, 518083, China.
- BGI Genomics, Shenzhen, 518083, China.
| | - Xin Tong
- BGI Research, Shenzhen, 518083, China
| | - Wei-Jian Mei
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Yanshuang Cheng
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Yuanqiang Zou
- BGI Research, Shenzhen, 518083, China
- Shenzhen Engineering Laboratory of Detection and Intervention of Human Intestinal Microbiome, Shenzhen, China
| | - Kai Han
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Jiehai Yu
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Zhuye Jie
- BGI Research, Shenzhen, 518083, China
| | - Tao Zhang
- BGI Research, Shenzhen, 518083, China
- Shenzhen Key Laboratory of Human commensal microorganisms and Health Research, Shenzhen, China
- BGI Research, Wuhan, 430074, China
| | - Shida Zhu
- BGI Genomics, Shenzhen, 518083, China
| | - Xin Jin
- BGI Research, Shenzhen, 518083, China
| | - Jian Wang
- BGI Research, Shenzhen, 518083, China
| | | | - Xun Xu
- BGI Research, Shenzhen, 518083, China
| | - Huanzi Zhong
- BGI Research, Shenzhen, 518083, China
- BGI Genomics, Shenzhen, 518083, China
| | - Liang Xiao
- BGI Research, Shenzhen, 518083, China
- Shenzhen Engineering Laboratory of Detection and Intervention of Human Intestinal Microbiome, Shenzhen, China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China.
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17
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Liu H, Xu H, Liu Y, Zhao Y, Zhang X, Yu Y, Du L, Liu Y, Wang W, Cao H, Ma L, Huang J, Cao J, Li L, Fan Y, Gu X, Feng C, Zhu Q, Wang X, Du J, Zhang S, Qiao Y. Comparative characteristics of early-onset vs. late-onset advanced colorectal cancer: a nationwide study in China. BMC Cancer 2024; 24:503. [PMID: 38643082 PMCID: PMC11031847 DOI: 10.1186/s12885-024-12278-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/17/2024] [Indexed: 04/22/2024] Open
Abstract
BACKGROUND The incidence of early-onset colorectal cancer (EOCRC, diagnosed in patients under the age of 50 years) has been increasing around the world. Here, we aimed to systematically identify distinctive features of EOCRC. METHODS From 2020 to 2021, we conducted a nationwide survey in 19 hospitals, collecting data on advanced CRC patients' demographics, clinical features, disease knowledge, medical experiences, expenditures, and health-related quality of life (HRQOL). We compared these features between EOCRC and late-onset colorectal cancer (LOCRC, ≥ 50 years old) groups and analyzed the association between EOCRC and HRQOL using multivariate linear regression. FINDINGS In total, 991 patients with EOCRC and 3581 patients with LOCRC were included. Compared to the LOCRC group, the EOCRC group had higher levels of education, were more informed about the risk factors for CRC, were more likely to have widespread metastases throughout the body, were more inclined to undergo gene testing, and were more likely to opt for targeted therapy, radiotherapy, and chemotherapy. However, HRQOL in the EOCRC group was similar to that of the LOCRC group, and no significant association was observed between EOCRC and HRQOL (beta: -0.753, P value: 0.307). INTERPRETATION In Chinese patients, EOCRC patients had more aggressive features. Despite undergoing more intensified treatments and gene testing, they had similar HRQOL compared with LOCRC. These findings advocate for a more tailored approach to treatment, especially for young CRC patients with advanced TNM stages and metastasis.
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Affiliation(s)
- Hongwei Liu
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Huifang Xu
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Yin Liu
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Yuqian Zhao
- Office of Academic Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Xi Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing Office for Cancer Prevention and Control, Peking University Cancer Hospital and Institute, Beijing, China
| | - Yanqin Yu
- The Clinical Epidemiology of Research Center, Department of Dermatological, The First Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Lingbin Du
- Department of Cancer Prevention, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yunyong Liu
- Office of Shenzhen Cancer Prevention and Control Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Wenjun Wang
- School of Nursing, Jining Medical University, Jining, China
| | - Helu Cao
- Department of Preventive Health, Xinxiang Central Hospital, Xinxiang, China
| | - Li Ma
- Public Health School, Dalian Medical University, Dalian, China
| | - Juanxiu Huang
- Department of Gastroenterology, Wuzhou Red Cross Hospital, Wuzhou, China
| | - Ji Cao
- Department of Cancer Prevention and Control Office, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Li Li
- Department of Clinical Research, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Yanping Fan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaofen Gu
- Department of Student Affairs, Affiliated Tumor Hospital, Xinjiang Medical University, Ürümqi, Xinjiang, China
| | - Changyan Feng
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Qian Zhu
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Xiaohui Wang
- Department of Public Health, Gansu Provincial Cancer Hospital, Lanzhou, China
| | - Jingchang Du
- School of Public Health, Chengdu Medical College, Chengdu, China
| | - Shaokai Zhang
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
| | - Youlin Qiao
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
- Center for Global Health, School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
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18
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Wu Y, Zhou J, Wang H, Fang G, Zhu W, Cai S, Wang L. Clinical and molecular heterogeneity associated with tumor sidedness in colorectal liver metastasis: a multicenter propensity cohort study. Hepatobiliary Surg Nutr 2024; 13:214-228. [PMID: 38617480 PMCID: PMC11007334 DOI: 10.21037/hbsn-22-285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 12/05/2022] [Indexed: 04/16/2024]
Abstract
Background Colorectal liver metastasis (CRLM) exhibits highly heterogeneity, with clinically and molecularly defined subgroups that differ in their prognosis. The aim of this study is to explore whether left-sided tumors is clinically and gnomically distinct from right-sided tumors in CRLM. Methods This retrospective study included 1,307 patients who underwent primary tumor and metastases resection at three academic centers in China from January 1, 2012, to December 31, 2020. Propensity score matching with 1:1 ratio matching was performed. The prognostic impact of tumor sidedness was determined after stratifying by the KRAS mutational status. Moreover, whole-exome sequencing (WES) of 200 liver tumor tissues were performed to describe the heterogeneity across the analysis of somatic and germline profiles. Results The median follow-up was 68 months. Matching yielded 481 pairs of patients. Compared to right-sided CRLM, left-sided patients experienced with better 5-year overall survival (OS) in surgery responsiveness, with a 14.6 lower risk of death [hazard ratio (HR), 1.36, 95% confidence interval (CI), 1.10-1.69, P=0.004]. Interaction between tumor sidedness and KRAS status was statistically significant: left-sidedness was associated with better prognosis among KRAS wild-type patients (HR 1.71; 95% CI: 1.20-2.45; P=0.003), but not among KRAS mutated-type patients. Integrated molecular analyses showed that right-sided tumors more frequently harbored TP53, APC, KRAS, and BRAF alterations, and identified a critical role of KRAS mutation in correlation with their survival differences. Higher pathogenic germline variants were identified in the right-sided tumors compared with left-sided tumors (29.3% vs. 15.5%, P=0.03). Conclusions We demonstrated that the prognostic impacts of tumor sidedness in CRLM is restricted patients with KRAS wild-type tumors. Tumor sidedness displays considerable clinical and molecular heterogeneity that may associate with their therapy benefits and prognosis.
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Affiliation(s)
- Yibin Wu
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Fudan University, Shanghai, China
| | - Jiamin Zhou
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Fudan University, Shanghai, China
| | - Huipeng Wang
- Department of General Surgery, Fifth People’s Hospital of Shanghai Fudan University, Shanghai, China
| | - Guojiu Fang
- Department of General Surgery, Shanghai Fengxian Central Hospital, Shanghai, China
| | - Weiping Zhu
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Fudan University, Shanghai, China
| | - Sanjun Cai
- Department of Oncology, Shanghai Medical College of Fudan University, Fudan University, Shanghai, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lu Wang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Fudan University, Shanghai, China
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19
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Jones AN, Scheurlen KM, Macleod A, Simon HL, Galandiuk S. Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer. Cancers (Basel) 2024; 16:1403. [PMID: 38611081 PMCID: PMC11010915 DOI: 10.3390/cancers16071403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/27/2024] [Accepted: 04/01/2024] [Indexed: 04/14/2024] Open
Abstract
Metabolic dysfunction associated with obesity leads to a chronic pro-inflammatory state with systemic effects, including the alteration of macrophage metabolism. Tumor-associated macrophages have been linked to the formation of cancer through the production of metabolites such as itaconate. Itaconate downregulates peroxisome proliferator-activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Similarly, leptin and adiponectin also influence macrophage cytokine expression and contribute to the progression of colorectal cancer via changes in gene expression within the PI3K/AKT pathway. This pathway influences cell proliferation, differentiation, and tumorigenesis. This work provides a review of obesity-related hormones and inflammatory mechanisms leading to the development and progression of early-onset colorectal cancer (EOCRC). A literature search was performed using the PubMed and Cochrane databases to identify studies related to obesity and EOCRC, with keywords including 'EOCRC', 'obesity', 'obesity-related hormones', 'itaconate', 'adiponectin', 'leptin', 'M2a macrophage', and 'microbiome'. With this concept of pro-inflammatory markers contributing to EOCRC, increased use of chemo-preventative agents such as aspirin may have a protective effect. Elucidating this association between obesity-related, hormone/cytokine-driven inflammatory effects with EOCRC may help lead to new therapeutic targets in preventing and treating EOCRC.
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Affiliation(s)
- Alexandra N. Jones
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
| | - Katharina M. Scheurlen
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
| | - Anne Macleod
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
| | - Hillary L. Simon
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
- Division of Colon and Rectal Surgery, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, KY 40202, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
- Division of Colon and Rectal Surgery, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, KY 40202, USA
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20
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Perea J, García JL, Corchete LA, Martí M, Hernández-Villafranca S, Alcázar JA, Álvaro E, Hurtado E, Jiménez-Toscano M, Balaguer F, Ballestero A, López-Rojo I, Jiménez F, Sanz G, Melone S, Brandáriz L, Vivas A, Alvarellos A, González-Sarmiento R. Chromosomal breaks: another differential gap between early-onset and late-onset colorectal cancers. Br J Surg 2024; 111:znae041. [PMID: 38430195 DOI: 10.1093/bjs/znae041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 03/03/2024]
Affiliation(s)
- José Perea
- Molecular Medicine Unit-Department of Medicine, Institute of Biomedical Research of Salamanca (IBSAL) and Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, Salamanca, Spain
- Surgery Department, Vithas Arturo Soria Hospital, Madrid, Spain
| | - Juan Luis García
- Molecular Medicine Unit-Department of Medicine, Institute of Biomedical Research of Salamanca (IBSAL) and Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, Salamanca, Spain
| | - Luis A Corchete
- Haematology Department, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Cancer Research Centre-IBMCC (USAL-CSIC), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Marc Martí
- Colorectal Unit, Vall d'Hebrón University Hospital, Barcelona, Spain
| | | | - José A Alcázar
- Surgery Department, Clinic University Hospital, Salamanca, Spain
| | - Edurne Álvaro
- Surgery Department, Infanta Leonor University Hospital, Madrid, Spain
| | - Elena Hurtado
- Surgery Department, Gregorio Marañon University Hospital, Madrid, Spain
| | | | - Francesc Balaguer
- Gastroenterology Department, Clinic University Hospital, Barcelona, Spain
| | | | - Irene López-Rojo
- Surgery Department, MD Anderson Cancer Center Madrid, Madrid, Spain
| | | | - Gonzalo Sanz
- Surgery Department, San Carlos University Hospital, Madrid, Spain
| | - Sirio Melone
- Surgery Department, Alcorcon Foundation Hospital, Madrid, Spain
| | | | - Alfredo Vivas
- Surgery Department, 12 de Octubre University Hospital, Madrid, Spain
| | - Alicia Alvarellos
- Surgery Department, University Clinic of Navarra-Madrid, Madrid, Spain
| | - Rogelio González-Sarmiento
- Molecular Medicine Unit-Department of Medicine, Institute of Biomedical Research of Salamanca (IBSAL) and Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, Salamanca, Spain
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21
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Wu Y, Zhuang J, Qu Z, Yang X, Han S. Advances in immunotyping of colorectal cancer. Front Immunol 2023; 14:1259461. [PMID: 37876934 PMCID: PMC10590894 DOI: 10.3389/fimmu.2023.1259461] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/22/2023] [Indexed: 10/26/2023] Open
Abstract
Immunotherapy has transformed treatment for various types of malignancy. However, the benefit of immunotherapy is limited to a minority of patients with mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) (dMMR-MSI-H) colorectal cancer (CRC). Understanding the complexity and heterogeneity of the tumor immune microenvironment (TIME) and identifying immune-related CRC subtypes will improve antitumor immunotherapy. Here, we review the current status of immunotherapy and typing schemes for CRC. Immune subtypes have been identified based on TIME and prognostic gene signatures that can both partially explain clinical responses to immune checkpoint inhibitors and the prognosis of patients with CRC. Identifying immune subtypes will improve understanding of complex CRC tumor heterogeneity and refine current immunotherapeutic strategies.
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Affiliation(s)
- Yinhang Wu
- Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer of Huzhou, Huzhou, China
- Huzhou Central Hospital, Fifth Affiliated Clinical Medical College of Zhejiang Chinese Medical University, Huzhou, China
| | - Jing Zhuang
- Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer of Huzhou, Huzhou, China
- Huzhou Central Hospital, Fifth Affiliated Clinical Medical College of Zhejiang Chinese Medical University, Huzhou, China
| | - Zhanbo Qu
- Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer of Huzhou, Huzhou, China
- Huzhou Central Hospital, Fifth Affiliated Clinical Medical College of Zhejiang Chinese Medical University, Huzhou, China
| | - Xi Yang
- Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer of Huzhou, Huzhou, China
- Huzhou Central Hospital, Fifth Affiliated Clinical Medical College of Zhejiang Chinese Medical University, Huzhou, China
| | - Shuwen Han
- Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer of Huzhou, Huzhou, China
- Huzhou Central Hospital, Fifth Affiliated Clinical Medical College of Zhejiang Chinese Medical University, Huzhou, China
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22
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Perea J, Gallagher P, Delores A. Lights and shadows in the early-onset colorectal cancer management and research: An integrative perspective - Physician scientist with patient advocates. Best Pract Res Clin Gastroenterol 2023; 66:101851. [PMID: 37852716 DOI: 10.1016/j.bpg.2023.101851] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/27/2023] [Accepted: 07/04/2023] [Indexed: 10/20/2023]
Abstract
Early-onset colorectal cancer (age under 50 years) (EOCRC) is an entity of undeniable importance, both because of its growing incidence, and the population it affects. Other current reviews emphasize the essential points regarding the clinical management and knowledge of its molecular bases. However, we intend to go one step further. With the increased significance of patient participation and disease experience in mind, we have integrated the voice of the patient to show the weaknesses and the needs, and next steps in the advancement of knowledge and management of EOCRC. This integrative review of the different perspectives, clinical, research and the patients themselves, can therefore be defined as an integrative needs assessment. Hence, this may be a first step in working towards an essential homogeneity of definitions and action.
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Affiliation(s)
- José Perea
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain; Department of Surgery. Vithas Arturo Soria University Hospital, Madrid, Spain.
| | | | - Annie Delores
- Fight Colorectal Cancer, USA; KRAS Kickers, USA; Colon Cancer Stars, USA
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23
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Ye T, Lin A, Qiu Z, Hu S, Zhou C, Liu Z, Cheng Q, Zhang J, Luo P. Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity. iScience 2023; 26:107045. [PMID: 37448561 PMCID: PMC10336167 DOI: 10.1016/j.isci.2023.107045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 03/17/2023] [Accepted: 06/01/2023] [Indexed: 07/15/2023] Open
Abstract
There is an urgent need for markers to predict the efficacy of different chemotherapy drugs. Herein, we examined whether microsatellite instability (MSI) status can predict tumor multidrug sensitivity and explored the underlying mechanisms. We downloaded data from several public databases. Drug sensitivity was compared between the high microsatellite instability (MSI-H) and microsatellite-stable/low microsatellite instability (MSS/MSI-L) groups. In addition, we performed pathway enrichment analysis and cellular chemosensitivity assays to explore the mechanisms by which MSI status may affect drug sensitivity and assessed the differences between drug-treated and control cell lines. We found that multiple MSI-H tumors were more sensitive to a variety of chemotherapy drugs than MSS/MSI-L tumors, and especially for CRC, chemosensitivity is enhanced through the downregulation of DDR pathways such as NHEJ. Additional DNA damage caused by chemotherapeutic drugs results in further downregulation of DDR pathways and enhances drug sensitivity, forming a cycle of increasing drug sensitivity.
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Affiliation(s)
- Taojun Ye
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengang Qiu
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shulu Hu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Chaozheng Zhou
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Zaoqu Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Quan Cheng
- Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
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24
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Medici B, Riccò B, Caffari E, Zaniboni S, Salati M, Spallanzani A, Garajovà I, Benatti S, Chiavelli C, Dominici M, Gelsomino F. Early Onset Metastatic Colorectal Cancer: Current Insights and Clinical Management of a Rising Condition. Cancers (Basel) 2023; 15:3509. [PMID: 37444619 DOI: 10.3390/cancers15133509] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include not only genetic syndromes but also other risk factors, such as microbiome alteration, antibiotic exposure, obesity, diabetes mellitus, and inflammatory bowel disease. EOCRC tends to be diagnosed later than in the older counterpart because of a lack of awareness and the fact that screening for CRC usually starts at the age of 50. Furthermore, CRC in young adults seems to be related to unique molecular features and more aggressive clinical behavior. This paper aims to provide an in-depth review of this poorly understood subject, with a comprehensive review of the state of the art and considerations for future perspectives.
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Affiliation(s)
- Bianca Medici
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Beatrice Riccò
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Eugenia Caffari
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Silvia Zaniboni
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Massimiliano Salati
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Ingrid Garajovà
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy
| | - Stefania Benatti
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Chiara Chiavelli
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Massimo Dominici
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
| | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy
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25
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Lu C, Zhang X, Schardey J, Wirth U, Heinrich K, Massiminio L, Cavestro GM, Neumann J, Bazhin AV, Werner J, Kühn F. Molecular characteristics of microsatellite stable early-onset colorectal cancer as predictors of prognosis and immunotherapeutic response. NPJ Precis Oncol 2023; 7:63. [PMID: 37393364 DOI: 10.1038/s41698-023-00414-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/15/2023] [Indexed: 07/03/2023] Open
Abstract
The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.
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Affiliation(s)
- Can Lu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention (Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for CANCER & Cancer Center of Zhejiang University, Hangzhou, China
| | - Xiaopeng Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Institute of Laboratory Medicine, University Hospital of LMU Munich, Munich, Germany
| | - Josefine Schardey
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
| | - Ulrich Wirth
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
| | - Luca Massiminio
- Experimental Gastroenterology Laboratory, Gastroenterology and Endoscopy Department, San Raffaele Scientific Institute, Milano, Italy
| | - Giulia Martina Cavestro
- Experimental Gastroenterology Laboratory, Gastroenterology and Endoscopy Department, San Raffaele Scientific Institute, Milano, Italy
| | - Jens Neumann
- Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany
| | - Florian Kühn
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany.
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany.
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany.
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Xiang M, Gao Y, Zhou Y, Wang M, Yao X. A novel nomogram based on cell cycle-related genes for predicting overall survival in early-onset colorectal cancer. BMC Cancer 2023; 23:595. [PMID: 37370046 DOI: 10.1186/s12885-023-11075-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Although the incidence of late-onset colorectal cancer (LOCRC) has decreased, the incidence of early-onset colorectal cancer (EOCRC) is still rising dramatically. Heterogeneity in the genomic, biological, and clinicopathological characteristics between EOCRC and LOCRC has been revealed. Therefore, the previous prognostic models based on the total CRC patient population might not be suitable for EOCRC patients. Here, we constructed a prognostic classifier to enhance the precision of individualized treatment and management of EOCRC patients. METHODS EOCRC expression data were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The regulatory pathways were explored by gene set enrichment analysis (GSEA). The prognostic model was developed by univariate Cox-LASSO-multivariate Cox regression analyses of GEO samples. TCGA samples were used to verify the model. The expression and mutation profiles and immune landscape of the high-risk and low-risk cohorts were analyzed and compared. Finally, the expression and prognostic value of the model genes were verified by immunohistochemistry and qRT‒PCR analysis. RESULTS The cell cycle was identified as the most significantly enriched oncological signature of EOCRC. Then, a 4-gene prognostic signature comprising MCM2, INHBA, CGREF1, and KLF9 was constructed. The risk score was an independent predictor of overall survival. The area under the curve values of the classifier for 1-, 3-, and 5-year survival were 0.856, 0.893, and 0.826, respectively, in the training set and 0.749, 0.858, and 0.865, respectively, in the validation set. Impaired DNA damage repair capability (p < 0.05) and frequent PIK3CA mutations (p < 0.05) were found in the high-risk cohort. CD8 T cells (p < 0.05), activated memory CD4 T cells (p < 0.01), and activated dendritic cells (p < 0.05) were clustered in the low-risk group. Finally, we verified the expression of MCM2, INHBA, CGREF1, and KLF9. Their prognostic value was closely related to age. CONCLUSION In this study, a robust prognostic classifier for EOCRC was established and validated. The findings may provide a reference for individualized treatment and medical decision-making for patients with EOCRC.
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Affiliation(s)
- Meijuan Xiang
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- Department of General Surgery, Foresea Life Insurance Shaoguan Hospital, Shaoguan, 512000, China
| | - Yuan Gao
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Yue Zhou
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Muqing Wang
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Xueqing Yao
- School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
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Su Y, Yang DS, Li YQ, Qin J, Liu L. Early-onset locally advanced rectal cancer characteristics, a practical nomogram and risk stratification system: a population-based study. Front Oncol 2023; 13:1190327. [PMID: 37260988 PMCID: PMC10228826 DOI: 10.3389/fonc.2023.1190327] [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: 03/20/2023] [Accepted: 04/26/2023] [Indexed: 06/02/2023] Open
Abstract
Background The purpose of this study is to construct a novel and practical nomogram and risk stratification system to accurately predict cancer-specific survival (CSS) of early-onset locally advanced rectal cancer (EO-LARC) patients. Methods A total of 2440 patients diagnosed with EO-LARC between 2010 and 2019 were screened from the Surveillance, Epidemiology, and End Results (SEER) database. The pool of potentially eligible patients was randomly divided into two groups: a training cohort (N=1708) and a validation cohort (N=732). The nomogram was developed and calibrated using various methods, including the coherence index (C-index), receiver operating characteristic curve (ROC), calibration curves, and decision curves (DCA). A new risk classification system was established based on the nomogram. To compare the performance of this nomogram to that of the American Joint Committee on Cancer (AJCC) staging system, DCA, net reclassification index (NRI), and integrated discrimination improvement (IDI) were employed. Result Seven variables were included in the model. The area under the ROC curve (AUC) for the training cohort was 0.766, 0.736, and 0.731 at 3, 6, and 9 years, respectively. Calibration plots displayed good consistency between actual observations and the nomogram's predictions. The DCA curve further demonstrated the validity of the nomination form in clinical practice. Based on the scores of the nomogram, all patients were divided into a low-risk group, a middle-risk group, and a high-risk group. NRI for the 3-, 6-, and 9-year CSS(training cohort: 0.48, 0.45, 0.52; validation cohort: 0.42, 0.37, 0.37), IDI for the 3-, 6-, and 9-year CSS (training cohort: 0.09, 0.10, 0.11; validation cohort: 0.07, 0.08, 0.08). The Kaplan-Meier curve revealed that the new risk classification system possesses a more extraordinary ability to identify patients in different risk groups than the AJCC staging. Conclusion A practical prognostic nomogram and novel risk classification system have been developed to efficiently predict the prognosis of EO-LARC. These tools can serve as a guide to individualize patient treatment and improve clinical decision-making.
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Affiliation(s)
- Yang Su
- Department of Gastrointestinal Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Da Shuai Yang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan qi Li
- Department of Gastrointestinal Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jichao Qin
- Department of Gastrointestinal Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Liu
- Department of Gastrointestinal Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Harrold E, Latham A, Pemmaraju N, Lieu CH. Early-Onset GI Cancers: Rising Trends, Genetic Risks, Novel Strategies, and Special Considerations. Am Soc Clin Oncol Educ Book 2023; 43:e398068. [PMID: 37235819 DOI: 10.1200/edbk_398068] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Cancers in young adults (commonly described as early-onset [EO] cancer) represent a group of malignancies that have unique and challenging biology and genetic, treatment, social, and psychological implications. Even more concerning is a rising trend of EO cancers in multiple tumor types. Research and investigation in EO cancers will help elucidate mechanisms of carcinogenesis, differences in biology and response to treatment, and the need for multidisciplinary care to ensure comprehensive treatment and support for young patients.
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Affiliation(s)
- Emily Harrold
- Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Alicia Latham
- Memorial Sloan-Kettering Cancer Center, New York, NY
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Moon JY, Kye BH, Ko SH, Yoo RN. Sulfur Metabolism of the Gut Microbiome and Colorectal Cancer: The Threat to the Younger Generation. Nutrients 2023; 15:nu15081966. [PMID: 37111185 PMCID: PMC10146533 DOI: 10.3390/nu15081966] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/13/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Colorectal cancer diagnosed in individuals under 50 years old is called early-onset colorectal cancer (EOCRC), and its incidence has been rising worldwide. Simultaneously occurring with increasing obesity, this worrisome trend is partly explained by the strong influence of dietary elements, particularly fatty, meaty, and sugary food. An animal-based diet, the so-called Western diet, causes a shift in dominant microbiota and their metabolic activity, which may disrupt the homeostasis of hydrogen sulfide concentration. Bacterial sulfur metabolism is recognized as a critical mechanism of EOCRC pathogenesis. This review evaluates the pathophysiology of how a diet-associated shift in gut microbiota, so-called the microbial sulfur diet, provokes injuries and inflammation to the colonic mucosa and contributes to the development of CRC.
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Affiliation(s)
- Ji-Yeon Moon
- Division of Colorectal Surgery, Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 442-723, Republic of Korea
| | - Bong-Hyeon Kye
- Division of Colorectal Surgery, Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 442-723, Republic of Korea
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon 442-723, Republic of Korea
| | - Ri Na Yoo
- Division of Colorectal Surgery, Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 442-723, Republic of Korea
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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.
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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
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Holowatyj AN, Wen W, Gibbs T, Seagle HM, Keller SR, Edwards DRV, Washington MK, Eng C, Perea J, Zheng W, Guo X. Racial/Ethnic and Sex Differences in Somatic Cancer Gene Mutations among Patients with Early-Onset Colorectal Cancer. Cancer Discov 2023; 13:570-579. [PMID: 36520636 PMCID: PMC10436779 DOI: 10.1158/2159-8290.cd-22-0764] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 11/07/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
UNLABELLED Molecular features underlying colorectal cancer disparities remain uncharacterized. Here, we investigated somatic mutation patterns by race/ethnicity and sex among 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients with colorectal cancer (2,016 early-onset colorectal cancer patients: sequencing age <50 years). NHB patients with early-onset nonhypermutated colorectal cancer, but not API patients, had higher adjusted tumor mutation rates than NHW patients. There were significant differences for LRP1B, FLT4, FBXW7, RNF43, ATRX, APC, and PIK3CA mutation frequencies in early-onset nonhypermutated colorectal cancers between racial/ethnic groups. Heterogeneities by race/ethnicity were observed for the effect of APC, FLT4, and FAT1 between early-onset and late-onset nonhypermutated colorectal cancer. By sex, heterogeneity was observed for the effect of EP300, BRAF, WRN, KRAS, AXIN2, and SMAD2. Males and females with nonhypermutated colorectal cancer had different trends in EP300 mutations by age group. These findings define genomic patterns of early-onset nonhypermutated colorectal cancer by race/ethnicity and sex, which yields novel biological clues into early-onset colorectal cancer disparities. SIGNIFICANCE NHBs, but not APIs, with early-onset nonhypermutated colorectal cancer had higher adjusted tumor mutation rates versus NHWs. Differences for FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in tumors of young patients. See related commentary by Shen et al., p. 530 . This article is highlighted in the In This Issue feature, p. 517.
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Affiliation(s)
- Andreana N. Holowatyj
- Department of Medicine, Microbiology and Immunology
- Vanderbilt-Ingram Cancer Center, Nashville, TN
- Vanderbilt University School of Medicine, Nashville, TN
| | - Wanqing Wen
- Department of Medicine, Microbiology and Immunology
| | | | - Hannah M. Seagle
- Department of Medicine, Microbiology and Immunology
- Vanderbilt University School of Medicine, Nashville, TN
| | - Samantha R. Keller
- Department of Medicine, Microbiology and Immunology
- Vanderbilt University School of Medicine, Nashville, TN
| | - Digna R. Velez Edwards
- Department of Obstetrics and Gynecology; Vanderbilt University Medical Center, Nashville, TN
| | - Mary K. Washington
- Department of Pathology, Microbiology and Immunology
- Vanderbilt-Ingram Cancer Center, Nashville, TN
| | - Cathy Eng
- Department of Medicine, Microbiology and Immunology
- Vanderbilt-Ingram Cancer Center, Nashville, TN
| | - Jose Perea
- Molecular Medicine Unit, Department of Medicine, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Department of Surgery, “Vithas Arturo Soria” University Hospital and School of Medicine, European University of Madrid, Madrid, Spain
| | - Wei Zheng
- Department of Medicine, Microbiology and Immunology
- Vanderbilt-Ingram Cancer Center, Nashville, TN
| | - Xingyi Guo
- Department of Medicine, Microbiology and Immunology
- Vanderbilt-Ingram Cancer Center, Nashville, TN
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Ha YJ, Shin YJ, Tak KH, Park JL, Kim JH, Lee JL, Yoon YS, Kim CW, Kim SY, Kim JC. Reduced expression of alanyl aminopeptidase is a robust biomarker of non-familial adenomatous polyposis and non-hereditary nonpolyposis colorectal cancer syndrome early-onset colorectal cancer. Cancer Med 2023; 12:10091-10104. [PMID: 36748835 PMCID: PMC10166950 DOI: 10.1002/cam4.5675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/20/2023] [Accepted: 01/27/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Early-onset colorectal cancer (EOCRC) has been increasing in incidence worldwide but its genomic pathogenesis is mostly undetermined. This study aimed to identify robust EOCRC-specific gene expression patterns in non-familial adenomatous polyposis (FAP) and non-hereditary nonpolyposis colorectal cancer syndrome (HNPCC) EOCRC. METHOD We first performed gene expression profiling analysis using RNA sequencing of discovery cohort comprised of 49 EOCRC (age <50) and 50 late-onset colorectal cancer (LOCRC) (age >70) specimens. To obtain robust gene expression data from this analysis, we validated differentially expressed genes (DEGs) through TCGA cohort (EOCRC:59 samples, LOCRC:229 samples) and our validation cohort (EOCRC:72 samples, LOCRC:43 samples) using real-time RT-PCR. After the validation of DEGs, we validated the selected gene at protein levels using Western blotting. To identify whether genomic methylation regulates the expression of a particular gene, we selected methylation sites using The Cancer Genome Atlas (TCGA) datasets and validated them by pyrosequencing in our validation cohort. RESULTS The EOCRC patients included in this study had significantly more prominent family history of cancer than the LOCRC patients (23 [46.9%] vs. 13 [26%], p = 0.050). Alanyl aminopeptidase (ANPEP) was significantly downregulated in the EOCRC tissues (FC = 1.78, p = 0.0007) and was also commonly downregulated in the TCGA cohort (FC = -1.08, p = 0.0021). Moreover, the ANPEP mRNA and protein expression levels were significantly downregulated in the EOCRC tissues of our validation cohort (p = 0.037 and 0.027). In comparisons of the normal and tumor tissues in public datasets, the ANPEP level was significantly lower in the tumor tissue in the TCGA dataset (p < 2.2 × 10-16 ) and GSE196006 dataset (p = 0.0005). Furthermore, the ANPEP expression level did not show a decreasing tendency at a young age in the normal colon tissue of the GTEx dataset. Lastly, the hypermethylation of cg26222247 in ANPEP was identified to be weakly associated with reduced ANPEP expression in our EOCRC cohort. CONCLUSION The reduced expression of ANPEP was identified as a novel biomarker of non-FAP and non-HNPCC EOCRC.
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Affiliation(s)
- Ye Jin Ha
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Yun Jae Shin
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.,Department of Bioinformatics, University of Science and Technology (UST), Daejeon, South Korea
| | - Ka Hee Tak
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Jong Lyul Park
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Jeong Hwan Kim
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Jong Lyul Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yong Sik Yoon
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chan Wook Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seon Young Kim
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.,Department of Bioinformatics, University of Science and Technology (UST), Daejeon, South Korea
| | - Jin Cheon Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Early Onset Colorectal Cancer in Arabs, Are We Dealing with a Distinct Disease? Cancers (Basel) 2023; 15:cancers15030889. [PMID: 36765846 PMCID: PMC9913248 DOI: 10.3390/cancers15030889] [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: 12/24/2022] [Revised: 01/23/2023] [Accepted: 01/26/2023] [Indexed: 02/05/2023] Open
Abstract
Early-onset colorectal cancer (EOCRC) incidence is increasing worldwide. Efforts are directed to understand the biological and clinical signatures of EOCRC compared to late-onset colorectal cancer (LOCRC). EOCRC is thought to present differently across different ethnic groups and geographical regions. This study was an attempt to contribute with data from the Arab world toward the understanding of the clinicopathological parameters of EOCRC compared to LOCRC. Data from 254 CRC patients diagnosed at Sultan Qaboos University Hospital from the period 2015-2020 were studied. About 32.6% of all diagnosed CRC patients are below 50 years old, with no differences in gender distribution between EOCRC and LOCRC (p-value 0.417). Rectal involvement and tumor laterality were comparable among the two groups. Adenocarcinoma accounts for 83.3% and 94.2% of EOCRC and LOCRC, respectively. More mucinous and signet ring adenocarcinoma (8.3% each) were reported in EOCRC than LOCRC (2.9% and 2.2%, respectively). MLH1 and PMS2 loss are more common among LOCRC, but MSH6 loss is more frequent in EOCRC. The overall survival of EOCRC and LOCRC was comparable (median survival 64.88 and 67.24 months, respectively). This study showed comparable clinicopathological parameters between EOCRC and LOCRC from Arabs, which adds to the bigger picture of understand the disease.
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New Personal Model for Forecasting the Outcome of Patients with Histological Grade III-IV Colorectal Cancer Based on Regional Lymph Nodes. JOURNAL OF ONCOLOGY 2023; 2023:6980548. [PMID: 36880007 PMCID: PMC9985509 DOI: 10.1155/2023/6980548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/27/2022] [Accepted: 11/24/2022] [Indexed: 02/27/2023]
Abstract
Background Metastases at regional lymph nodes could easily occur in patients with high-histological-grade colorectal cancer (CRC). However, few models were built on the basis of lymph nodes to predict the outcome of patients with histological grades III-IV CRC. Methods Data in the Surveillance, Epidemiology, and End Results databases were used. Univariate and multivariate analyses were performed. A personalized prediction model was built in accordance with the results of the analyses. A nomogram was tested in two datasets and assessed using a calibration curve, a consistency index (C-index), and an area under the curve (AUC). Results A total of 14,039 cases were obtained from the database. They were separated into two groups (9828 cases for constructing the model and 4211 cases for validation). Logistic and Cox regression analyses were then conducted. Factors such as log odds of positive lymph nodes (LODDS) were utilized. Then, a personalized prediction model was established. The C-index in the construction and validation groups was 0.770. The 1-, 3-, and 5-year AUCs were 0793, 0.828, and 0.830 in the construction group, respectively, and 0.796, 0.833, and 0.832 in the validation group, respectively. The calibration curves showed well consistency in the 1-, 3- and 5-year OS between prediction and reality in both groups. Conclusion The nomogram built based on LODDS exhibited considerable reliability and accuracy.
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Kim D, Cho KH. Hidden patterns of gene expression provide prognostic insight for colorectal cancer. Cancer Gene Ther 2023; 30:11-21. [PMID: 35982221 DOI: 10.1038/s41417-022-00520-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 07/15/2022] [Accepted: 08/04/2022] [Indexed: 01/19/2023]
Abstract
Cancer tissue samples contain cancer cells and non-cancer cells with each biopsied site containing distinct proportions of these populations. Consequently, assigning useful tumor subtypes based on gene expression measurements from clinical samples is challenging. We applied a blind source separation approach to extract cancer cell-intrinsic gene expression patterns within clinical tumor samples of colorectal cancer. After a blind source separation, we found that a cancer cell-intrinsic gene expression program unique to each patient exists in the "residual" expression profile remaining after separation of the gene expression data. We performed a consensus clustering analysis of the extracted gene expression profiles to identify novel and robust cancer cell-intrinsic subtypes. We validated the identified subtypes using an independent clinical gene expression dataset. The cancer cell-intrinsic subtypes are independent of biopsy site and provided prognostic information in addition to currently available clinical and molecular variables. After validating this approach in colorectal cancer, we further identified novel tumor subtypes with unique clinical information across multiple types of cancer. These cancer cell-intrinsic molecular subtypes provide novel prognostic value for clinical assessment of cancer.
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Affiliation(s)
- Dongsan Kim
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Kwang-Hyun Cho
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
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36
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Li GM, Xiao GZ, Qin PF, Wan XY, Fu YJ, Zheng YH, Luo MY, Ren DL, Liu SP, Chen HX, Lin HC. Single-Cell RNA Sequencing Reveals Heterogeneity in the Tumor Microenvironment between Young-Onset and Old-Onset Colorectal Cancer. Biomolecules 2022; 12:biom12121860. [PMID: 36551288 PMCID: PMC9776336 DOI: 10.3390/biom12121860] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/04/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The incidence of sporadic young-onset colorectal cancer (yCRC) is increasing. Compared with old-onset colorectal cancer (oCRC), yCRC has different clinical and molecular characteristics. However, the difference in the tumor microenvironment (TME) between yCRC and oCRC remains unclear. METHODS Fourteen untreated CRC tumor samples were subjected to single-cell RNA sequencing analysis. RESULTS B cells and naïve T cells are enriched in yCRC, while effector T cells and plasma cells are enriched in oCRC. Effector T cells of yCRC show decreased interferon-gamma response and proliferative activity; meanwhile, Treg cells in yCRC show stronger oxidative phosphorylation and TGF-β signaling than that in oCRC. The down-regulated immune response of T cells in yCRC may be regulated by immune and malignant cells, as we observed a downregulation of antigen presentation and immune activations in B cells, dendritic cells, and macrophages. Finally, we identified malignant cells in yCRC and oCRC with high heterogeneity and revealed their interactions with immune cells in the TME. CONCLUSIONS Our data reveal significant differences of TME between yCRC and oCRC, of which the TME of yCRC is more immunosuppressive than oCRC. Malignant cells play an essential role in the formation of the suppressive tumor immune microenvironment.
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Affiliation(s)
- Gui-Ming Li
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
| | - Guo-Zhong Xiao
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
| | - Peng-Fei Qin
- BGI-Shenzhen, Beishan Industrial Zone, Shenzhen 518083, China
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China
- Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen 518083, China
| | - Xing-Yang Wan
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
| | - Yuan-Ji Fu
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
| | - Yi-Hui Zheng
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
| | - Min-Yi Luo
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
| | - Dong-Lin Ren
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
| | - Shi-Ping Liu
- BGI-Shenzhen, Beishan Industrial Zone, Shenzhen 518083, China
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China
- Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen 518083, China
- Correspondence: (S.-P.L.); (H.-X.C.); (H.-C.L.); Tel.: +86-15915815776 (H.-C.L.); Fax: +86-20-38254221 (H.-C.L.)
| | - Hua-Xian Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Correspondence: (S.-P.L.); (H.-X.C.); (H.-C.L.); Tel.: +86-15915815776 (H.-C.L.); Fax: +86-20-38254221 (H.-C.L.)
| | - Hong-Cheng Lin
- Department of Colorectal Surgery, 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
- Guangdong Institute of Gastroenterology, Guangzhou 510655, China
- Correspondence: (S.-P.L.); (H.-X.C.); (H.-C.L.); Tel.: +86-15915815776 (H.-C.L.); Fax: +86-20-38254221 (H.-C.L.)
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Hamilton AC, Bannon FJ, Dunne PD, James J, McQuaid S, Gray RT, Salto-Tellez M, Cardwell CR, Loughrey MB, Coleman HG. Distinct Molecular Profiles of Sporadic Early-Onset Colorectal Cancer: A Population-Based Cohort and Systematic Review. GASTRO HEP ADVANCES 2022; 2:347-359. [PMID: 39132649 PMCID: PMC11307521 DOI: 10.1016/j.gastha.2022.11.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/02/2022] [Indexed: 08/13/2024]
Abstract
BACKGROUND AND AIMS The observed increase in the incidence of early-onset colorectal cancer (EOCRC) is being driven by sporadic cases, but the molecular characteristics of these tumors are not fully understood. Our objective was to investigate the prevalence of microsatellite instability (MSI) and selected mutations in sporadic EOCRC, and their association with survival. METHODS Firstly, we compared the prevalence of molecular characteristics and survival within a population-based cohort study of 652 stage II and III colon cancer patients in Northern Ireland, comparing sporadic early-onset (<50 years, n = 35) with older (60-69 years, n = 179) patients. Secondly, a systematic review for studies reporting the prevalence of MSI, mismatch repair deficiency (dMMR), or BRAF, KRAS, NRAS, PIK3CA, and TP53 mutations in sporadic EOCRC was conducted. A meta-analysis was performed to calculate pooled estimates of the prevalence of molecular features in sporadic EOCRC. RESULTS Firstly, within the cohort study, EOCRC patients did not have a significantly increased risk of colorectal cancer-specific death (adjusted hazard ratio 1.20; 95% confidence interval [CI] 0.61-2.39) compared with 60- to 69-year-olds. Second, 32 studies were included in the systematic review. The pooled analysis estimated a prevalence of 10% (95% CI 7%-14%) for MSI high/dMMR in sporadic EOCRC. BRAF and KRAS mutations had a prevalence of 1% (95% CI 0%-3%) and 32% (95% CI 23%-40%), respectively. CONCLUSION The molecular characteristics of sporadic EOCRC differ from those of cancers in older adults, particularly regarding reduced prevalence of BRAF mutations. Ten percent of sporadic EOCRC display MSI high/dMMR. Further studies are needed to address survival in sporadic EOCRC cases and whether molecular profiles influence EOCRC outcomes in this patient group.
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Affiliation(s)
| | - Finian J. Bannon
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
| | - Philip D. Dunne
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- CRUK Beatson Institute, Glasgow, UK
| | - Jacqueline James
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Northern Ireland Biobank, Belfast, Northern Ireland, UK
- Precision Medicine Centre of Excellence, Queen’s University Belfast, Northern Ireland, UK
| | - Stephen McQuaid
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Northern Ireland Biobank, Belfast, Northern Ireland, UK
| | - Ronan T. Gray
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
- South Eastern Health and Social Care Trust, Northern Ireland, UK
| | - Manuel Salto-Tellez
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Precision Medicine Centre of Excellence, Queen’s University Belfast, Northern Ireland, UK
| | - Chris R. Cardwell
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
| | - Maurice B. Loughrey
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Department of Cellular Pathology, Belfast Health and Social Care Trust, Northern Ireland, UK
| | - Helen G. Coleman
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
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Nakamura K, Hernández G, Sharma GG, Wada Y, Banwait JK, González N, Perea J, Balaguer F, Takamaru H, Saito Y, Toiyama Y, Kodera Y, Boland CR, Bujanda L, Quintero E, Goel A. A Liquid Biopsy Signature for the Detection of Patients With Early-Onset Colorectal Cancer. Gastroenterology 2022; 163:1242-1251.e2. [PMID: 35850198 PMCID: PMC9613521 DOI: 10.1053/j.gastro.2022.06.089] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/18/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Early-onset colorectal cancer (EOCRC) is a distinct clinical and molecular entity with poor survival outcomes compared with late-onset CRC. Although the incidence of EOCRC is rising, current CRC screening strategies have several limitations in diagnostic performance for EOCRC. In view of this clinical challenge, novel and robust biomarkers for detection of EOCRC are necessary. The aim of this study was to develop a circulating micro RNA (miRNA) signature for the diagnosis of patients with EOCRC. METHODS A systematic discovery approach by analyzing a large, publicly available, noncoding RNA expression profiling dataset (GSE115513) was used. A panel of miRNAs was identified, which was subsequently validated in blood samples from patients with EOCRC in 2 independent cohorts (n = 149) compared with controls (n = 110) and pre/postoperative plasma specimens (n = 22) using quantitative reverse-transcription polymerase chain reaction assays. RESULTS In the discovery phase, 4 miRNAs were found to be expressed in blood samples. A combination signature of these 4 miRNAs (miR-193a-5p, miR-210, miR-513a-5p, and miR-628-3p) yielded an area under the curve of 0.92 (95% confidence interval, 0.85-0.96) for identification of EOCRC in the training cohort. The miRNA panel performance was then confirmed in an independent validation cohort (area under the curve, 0.88; 95% confidence interval, 0.82-0.93). Moreover, the miRNA panel robustly identified patients with early-stage EOCRC (P < .001). The decreased expression of miRNAs in postsurgery plasma specimens indicated their tumor specificity. CONCLUSIONS Our novel miRNA signature for the diagnosis of EOCRC has the potential to identify patients with EOCRC with high accuracy for clinical application in the noninvasive diagnosis of EOCRC.
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Affiliation(s)
- Kota Nakamura
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California; Department of Surgery, Nara Medical University, Nara, Japan
| | - Goretti Hernández
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Gastroenterology Department, Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB) and Centro de Investigación Biomédica de Canarias (CIBICAN), Departamento de Medicina Interna, Universidad de La Laguna, Santa Cruz de Tenerife, Tenerife, Spain
| | - Geeta G Sharma
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California
| | - Yuma Wada
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California; Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Jasjit K Banwait
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Natalia González
- Gastroenterology Department, Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB) and Centro de Investigación Biomédica de Canarias (CIBICAN), Departamento de Medicina Interna, Universidad de La Laguna, Santa Cruz de Tenerife, Tenerife, Spain
| | - Jose Perea
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Fundación Jiménez Díaz University Hospital Health Research Institute, Madrid, Spain
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | | | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - C Richard Boland
- Division of Gastroenterology, School of Medicine, University of California San Diego, La Jolla, California
| | - Luis Bujanda
- Gastroenterology Department, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Enrique Quintero
- Gastroenterology Department, Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB) and Centro de Investigación Biomédica de Canarias (CIBICAN), Departamento de Medicina Interna, Universidad de La Laguna, Santa Cruz de Tenerife, Tenerife, Spain
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California; Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; City of Hope Comprehensive Cancer Center, Duarte, California.
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Hu C, Cai D, Zhong ME, Fan D, Li CH, Lv MY, Huang ZP, Wang W, Wu XJ, Gao F. Predicting prognosis and immunotherapy response among colorectal cancer patients based on a tumor immune microenvironment-related lncRNA signature. Front Genet 2022; 13:993714. [PMID: 36159987 PMCID: PMC9489948 DOI: 10.3389/fgene.2022.993714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) remodel the tumor immune microenvironment (TIME) by regulating the functions of tumor-infiltrating immune cells. It remains uncertain the way that TIME-related lncRNAs (TRLs) influence the prognosis and immunotherapy response of colorectal cancer (CRC). Aiming at providing survival and immunotherapy response predictions, a CRC TIME-related lncRNA signature (TRLs signature) was developed and the related potential regulatory mechanisms were explored with a comprehensive analysis on gene expression profiles from 97 immune cell lines, 61 CRC cell lines and 1807 CRC patients. Stratifying CRC patients with the TRLs signature, prolonged survival was observed in the low-risk group, while the patients in the high-risk group had significantly higher pro-tumor immune cells infiltration and higher immunotherapy response rate. Through the complex TRLs-mRNA regulation network, immunoregulation pathways and immunotherapy response pathways were found to be differently activated between the groups. In conclusion, the CRC TRLs signature is capable of making prognosis and immunotherapy response predictions, which may find application in stratifying patients for immunotherapy in the bedside.
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Affiliation(s)
- Chuling Hu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Du Cai
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Min-Er Zhong
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dejun Fan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cheng-Hang Li
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Min-Yi Lv
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ze-Ping Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Wang
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiao-Jian Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Xiao-Jian Wu, ; Feng Gao,
| | - Feng Gao
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Xiao-Jian Wu, ; Feng Gao,
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Mao Y, Xu Y, Chang J, Chang W, Lv Y, Zheng P, Zhang Z, Li Z, Lin Q, Tang W, Zhu D, Ji M, He G, Feng Q, Xu J. The immune phenotypes and different immune escape mechanisms in colorectal cancer. Front Immunol 2022; 13:968089. [PMID: 36032084 PMCID: PMC9399611 DOI: 10.3389/fimmu.2022.968089] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
The tumor microenvironment (TME) plays a crucial role in tumor progression and metastasis. However, the immune phenotypes of colorectal cancer (CRC) and the underlying immune escape mechanism have not been studied sufficiently. A total of 1802 and 619 CRC samples from the microarray and TCGA cohorts were enrolled, respectively. The ssGSEA algorithm and unsupervised clustering were used for TME cell infiltration speculation and immune phenotype recognition in the above cohorts. A total of 447 samples from Zhongshan Hospital were collected for validation. Immunohistochemistry was performed in this cohort to quantify TME cell infiltration. The single-cell RNA-seq (scRNA-seq) data of 252,940 cells from 60 CRC samples was analyzed for further mechanistic exploration. CRC samples can be classified into three distinct immune phenotypes. Subtype 1, the immune-active subtype, was characterized by high infiltration of activated adaptive immune cells. Subtype 2, the immune-desert subtype, featured high tumor purity and low infiltration of immune and stromal cells. Subtype 3, the stroma-rich subtype, had high infiltration of stromal cells. The stroma-rich subtype conferred a significantly worse prognosis. The three subtypes had different immune escape mechanisms. The immune-active subtype has the highest immune checkpoint expression level. In comparison, the immune-desert subtype had the lowest immunogenicity and defective antigen presentation. The stroma-rich subtype lacked activated immune cells. In conclusion, distinct immune phenotypes and immune escape mechanisms may provide inspiration and direction for further research on CRC immunotherapy.
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Affiliation(s)
- Yihao Mao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuqiu Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiang Chang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenju Chang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Yang Lv
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peng Zheng
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiyuan Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiqiang Li
- Department of General Surgery, No.2 Hospital, Nanping, China
| | - Qi Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Wentao Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Dexiang Zhu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Meiling Ji
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Guodong He
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Qingyang Feng
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
- *Correspondence: Qingyang Feng, ; Jianmin Xu,
| | - Jianmin Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
- *Correspondence: Qingyang Feng, ; Jianmin Xu,
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Abstract
Contrary to decreasing incidence rate of colorectal cancer (CRC) in older adults, incidence rates have nearly doubled in younger adults (age <50 years) in the United States since the early 1990s. A similar increase has been observed across the globe. Despite overall population trends in aging, about 15% of CRCs will be diagnosed in younger adults by 2030. The mechanisms and factors contributing to early-onset CRC (EOCRC) remain puzzling, especially because most young adults diagnosed with CRC have no known risk factors or predisposing conditions, such as family history of CRC or polyps or a hereditary syndrome (eg, Lynch syndrome, polyposis). In this up-to-date review, we discuss the current knowledge of EOCRC, including epidemiology, risk factors, clinical and molecular features, treatment and survival, and recognition and screening strategies.
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Affiliation(s)
- Pooja Dharwadkar
- Division of Gastroenterology, Department of Medicine, University of California San Francisco, Zuckerberg San Francisco General, Building 5, 3rd Floor, Suite 3D, 1001 Potrero Avenue, San Francisco, CA 94110, USA
| | - Timothy A Zaki
- Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Caitlin C Murphy
- UTHealth School of Public Health, Suite 2618, 7000 Fannin Street, Houston, TX 77030, USA.
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Pretzsch E, Nieß H, Bösch F, Westphalen C, Jacob S, Neumann J, Werner J, Heinemann V, Angele M. Age and metastasis – How age influences metastatic spread in cancer. Colorectal cancer as a model. Cancer Epidemiol 2022; 77:102112. [PMID: 35104771 DOI: 10.1016/j.canep.2022.102112] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 12/12/2022]
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44
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Gu J, Li Y, Yu J, Hu M, Ji Y, Li L, Hu C, Wei G, Huo J. A risk scoring system to predict the individual incidence of early-onset colorectal cancer. BMC Cancer 2022; 22:122. [PMID: 35093005 PMCID: PMC8801093 DOI: 10.1186/s12885-022-09238-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 01/20/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND The incidence of early-onset colorectal cancer (EOCRC) is increasing at an alarming rate and further studies are needed to identify risk factors and to develop prevention strategies. METHODS Risk factors significantly associated with EOCRC were identified using meta-analysis. An individual risk appraisal model was constructed using the Rothman-Keller model. Next, a group of random data sets was generated using the binomial distribution function method, to determine nodes of risk assessment levels and to identify low, medium, and high risk populations. RESULTS A total of 32,843 EOCRC patients were identified in this study, and nine significant risk factors were identified using meta-analysis, including male sex, Caucasian ethnicity, sedentary lifestyle, inflammatory bowel disease, and high intake of red meat and processed meat. After simulating the risk assessment data of 10,000 subjects, scores of 0 to 0.0018, 0.0018 to 0.0036, and 0.0036 or more were respectively considered as low-, moderate-, and high-risk populations for the EOCRC population based on risk trends from the Rothman-Keller model. CONCLUSION This model can be used for screening of young adults to predict high risk of EOCRC and will contribute to the primary prevention strategies and the reduction of risk of developing EOCRC.
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Affiliation(s)
- Jialin Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China
- Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, China
| | - Yan Li
- Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, China
| | - Jialin Yu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China
- Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China
| | - Miao Hu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China
- Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, China
| | - Yi Ji
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China
- Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China
| | - Lingchang Li
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China
- Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China
| | - Canhong Hu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China
- Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China
| | - Guoli Wei
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China.
- Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
- Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, Jiangsu, China.
- Yangzhou University Medical College, Yangzhou, 225000, Jiangsu, China.
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Cross Street, Maigaoqiao, Nanjing, Jiangsu, 210028, P.R. China.
- Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
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Eng C, Jácome AA, Agarwal R, Hayat MH, Byndloss MX, Holowatyj AN, Bailey C, Lieu CH. A comprehensive framework for early-onset colorectal cancer research. Lancet Oncol 2022; 23:e116-e128. [PMID: 35090673 DOI: 10.1016/s1470-2045(21)00588-x] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 02/07/2023]
Abstract
Sporadic colorectal cancer has traditionally been viewed as a malignancy of older individuals. However, as the global prevalence of the disease diagnosed in younger individuals (<50 years) is expected to increase within the next decade, greater recognition is now being given to early-onset colorectal cancer. The cause of the predicted rise in prevalence is largely unknown and probably multifactorial. In this Series paper, we discuss the potential underlying causes of early-onset colorectal cancer, the role of energy balance, biological and genomic mechanisms (including microbiome aspects), and the treatment of early-onset colorectal cancer. We have specifically considered the psychosocial challenges of being diagnosed with colorectal cancer at younger age and the potential financial toxicity that might ensue. This Series paper brings a comprehensive review based on the existing data in the hopes of optimising the overall outcomes for patients with early-onset colorectal cancer.
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Jaffrelot M, Farés N, Brunac AC, Laurenty AP, Danjoux M, Grand D, Icher S, Meilleroux J, Mery E, Buscail E, Maulat C, Toulas C, Vande Perre P, Chipoulet E, Bonnet D, Staub A, Guimbaud R, Selves J. An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod Pathol 2022; 35:427-437. [PMID: 34545179 PMCID: PMC8860743 DOI: 10.1038/s41379-021-00918-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 08/21/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023]
Abstract
Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.
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Affiliation(s)
- Marion Jaffrelot
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Nadim Farés
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France ,grid.15781.3a0000 0001 0723 035XUniversité Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330 Toulouse, France ,grid.411175.70000 0001 1457 2980Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Cécile Brunac
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Pascale Laurenty
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Marie Danjoux
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - David Grand
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Samira Icher
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Julie Meilleroux
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Eliane Mery
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Etienne Buscail
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Charlotte Maulat
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Christine Toulas
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Pierre Vande Perre
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Edith Chipoulet
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Delphine Bonnet
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Staub
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Rosine Guimbaud
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France ,grid.15781.3a0000 0001 0723 035XUniversité Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330 Toulouse, France ,grid.411175.70000 0001 1457 2980Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Janick Selves
- Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330, Toulouse, France. .,Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France.
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Cercek A, Chatila WK, Yaeger R, Walch H, Fernandes GDS, Krishnan A, Palmaira L, Maio A, Kemel Y, Srinivasan P, Bandlamudi C, Salo-Mullen E, Tejada PR, Belanfanti K, Galle J, Joseph V, Segal N, Varghese A, Reidy-Lagunes D, Shia J, Vakiani E, Mondaca S, Mendelsohn R, Lumish MA, Steinruecke F, Kemeny N, Connell L, Ganesh K, Markowitz A, Nash G, Guillem J, Smith JJ, Paty PB, Zhang L, Mandelker D, Birsoy O, Robson M, Offit K, Taylor B, Berger M, Solit D, Weiser M, Saltz LB, Aguilar JG, Schultz N, Diaz LA, Stadler ZK. A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers. J Natl Cancer Inst 2021; 113:1683-1692. [PMID: 34405229 PMCID: PMC8634406 DOI: 10.1093/jnci/djab124] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/29/2021] [Accepted: 06/04/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). METHODS Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. RESULTS In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36-49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36-49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01). CONCLUSIONS EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.
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Affiliation(s)
- Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Walid K Chatila
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Henry Walch
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Asha Krishnan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lerie Palmaira
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anna Maio
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yelena Kemel
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Preethi Srinivasan
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chaitanya Bandlamudi
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Erin Salo-Mullen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Prince R Tejada
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kimeisha Belanfanti
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jesse Galle
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vijai Joseph
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Neil Segal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anna Varghese
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Diane Reidy-Lagunes
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Efsevia Vakiani
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sebastian Mondaca
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Robin Mendelsohn
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melissa A Lumish
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Felix Steinruecke
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nancy Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Louise Connell
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Karuna Ganesh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Arnold Markowitz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Garrett Nash
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jose Guillem
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - J Joshua Smith
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Phillip B Paty
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Liying Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Diana Mandelker
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ozge Birsoy
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark Robson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Offit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Barry Taylor
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Berger
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David Solit
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Martin Weiser
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Leonard B Saltz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julio Garcia Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikolaus Schultz
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Luis A Diaz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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McClelland PHT, Liu T, Ozuner G. Early-Onset Colorectal Cancer in Patients under 50 Years of Age: Demographics, Disease Characteristics, and Survival. Clin Colorectal Cancer 2021; 21:e135-e144. [PMID: 34972664 DOI: 10.1016/j.clcc.2021.11.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 10/05/2021] [Accepted: 11/22/2021] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Incidence of early-onset colorectal cancer (EO-CRC) is increasing in younger demographics. This study analyzes disease-specific survival in individuals under 50 years of age. METHODS Patients with colorectal malignancy were identified in the Surveillance Epidemiology and End Results (SEER) database from 2004 to 2015. Cases were categorized into typically screened (age 50-79 years) and non-typically screened (age 20-49 years) cohorts, as well as by decade. Kaplan-Meier curves and Cox proportional hazard models were used to study survival. RESULTS A total of 240,772 patients with colorectal cancer were analyzed. Average annual percent change in incidence was -0.24% among typically screened patients and +1.12% among patients with EO-CRC. Patients with EO-CRC more frequently presented with distal tumors (70.6% vs. 57.6%, P < .001) and advanced tumor stage (61.3% vs. 48.6%, P < .001). Patients aged 50 and over had comparable 5 year disease-specific survival to younger patients (68.2% vs. 66.4%, P = .31); however, patients in the 3rd, 4th, and 8th decade of life had particularly low survival rates (59.0% vs. 65.8% vs. 65.8%, logrank P < .001). Patients aged 20-29 years had the most increased risk of cause-specific mortality on univariable Cox regression analysis [HR 1.43, 95% CI 1.31-1.56; P < .001], although this was not significant on multivariable analysis [HR 1.06, 95% CI 0.97-1.15; P = .201]. Male sex, older age, advanced stage, rectal and/or cecal primary, and earlier year of diagnosis were independently associated with increased mortality. CONCLUSION Patients with EO-CRC are diagnosed at a later stage and have lower disease-specific survival than those in typically screened cohorts. Additional studies on tumor biology and surveillance strategies are needed to improve outcomes in this population.
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Affiliation(s)
| | - Tianming Liu
- Department of Surgery, Baylor College of Medicine, Houston, TX
| | - Gokhan Ozuner
- Department of Surgery, Hackensack Meridian Health, North Bergen, NJ
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Escobar D, Bushara O, Sun L, Liao J, Yang GY. Clinicopathologic Characteristics of FBXW7-Mutated Colorectal Adenocarcinoma and Association with Aberrant Beta-catenin Localization. Hum Pathol 2021; 119:51-58. [PMID: 34717891 DOI: 10.1016/j.humpath.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/06/2021] [Indexed: 11/04/2022]
Abstract
Oncogenic mutations in the adenomatous polyposis coli (APC)/Wnt signaling pathway are well documented. The FBXW7 gene (F-Box And WD Repeat Domain Containing 7) encodes a member of the ubiquitin-proteasome complex that is more recently described to antagonize the oncogenic Wnt pathway by promoting the degradation of β-catenin encoded by CTNNB1 gene. The pathologic significance of FBXW7 mutation in colorectal carcinoma (CRC) remains underreported. In this study, we report the clinicopathologic and β-catenin immunohistochemical features of a single-institution cohort (83 cases) of FBXW7-mutated CRC compared to CTNNB1-mutated CRC. FBXW7-mutated CRC was more common in older patients (p=0.031) and in the left/distal colon (p=0.022). Immunohistochemical analysis revealed that aberrant nuclear/cytoplasmic β-catenin localization was identified in a significantly high proportion of FBXW7-mutated CRCs. When compared to CTNNB1-mutated CRC, FBXW7-mutated CRC showed a significantly higher proportion of MSI-stable tumors with intact expression of DNA mismatch repair proteins, and had significantly more frequent co-occurrence of missense TP53 and KRAS mutations. The most frequently mutated FBXW7 residues/hotspots were located within the WD repeat domains (aa 378-659), which were also associated with aberrant nuclear/cytoplasmic localization of β-catenin protein. Our results indicate the unique pathologic characteristics of FBXW7 mutated CRC with frequent co-occurrence of missense mutant TP53, and KRAS. The mutated FBXW7 residues/hotspots and its association with aberrant nuclear/cytoplasmic β-catenin localization further support the oncogenic role of FBXW7 in colon carcinogenesis.
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Affiliation(s)
- David Escobar
- Department of Pathology, Northwestern University, Feinberg School of Medicine
| | - Omar Bushara
- Department of Pathology, Northwestern University, Feinberg School of Medicine
| | - Leyu Sun
- Department of Pathology, Northwestern University, Feinberg School of Medicine
| | - Jie Liao
- Department of Pathology, Northwestern University, Feinberg School of Medicine
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University, Feinberg School of Medicine.
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50
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Tian S, Wang F, Zhang R, Chen G. Global Pattern of CD8 + T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response. Front Pharmacol 2021; 12:715721. [PMID: 34594218 PMCID: PMC8477790 DOI: 10.3389/fphar.2021.715721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/22/2021] [Indexed: 01/22/2023] Open
Abstract
Background: The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response. Methods: We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8+ T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8+ T cells in different exhaustion states. Results: TMEPRE showed predictive power in three datasets of anti-PD1-treated patients (p = 0.056, 0.115, 0.003). CD8+ T-cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection (p = 0.048, 0.001). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer. Conclusion: TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8+ T-cell infiltration and CD8+ T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8+ T cells or terminal exhaustion of CD8+ T cells need different treatment strategies.
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Affiliation(s)
- Sun Tian
- Carbon Logic Biotech (HK) Limited, Hongkong, China
| | - Fulong Wang
- StateKey Laboratory of Oncology in South China, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Rongxin Zhang
- StateKey Laboratory of Oncology in South China, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Gong Chen
- StateKey Laboratory of Oncology in South China, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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