Abstract
Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics. Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation. Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70–0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15–3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages. Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 229-245 |
| Number of pages | 17 |
| Journal | Journal of gastroenterology |
| Volume | 58 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2023 |
Keywords
- Biogeography
- Epigenetics
- Mismatch repair
- Molecular pathological epidemiology
- Young-onset cancer
ASJC Scopus subject areas
- Gastroenterology
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Prognostic role of detailed colorectal location and tumor molecular features : analyses of 13,101 colorectal cancer patients including 2994 early-onset cases. / Ugai, Tomotaka; Akimoto, Naohiko; Haruki, Koichiro et al.
In: Journal of gastroenterology, Vol. 58, No. 3, 03.2023, p. 229-245.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Prognostic role of detailed colorectal location and tumor molecular features
T2 - analyses of 13,101 colorectal cancer patients including 2994 early-onset cases
AU - Ugai, Tomotaka
AU - Akimoto, Naohiko
AU - Haruki, Koichiro
AU - Harrison, Tabitha A.
AU - Cao, Yin
AU - Qu, Conghui
AU - Chan, Andrew T.
AU - Campbell, Peter T.
AU - Berndt, Sonja I.
AU - Buchanan, Daniel D.
AU - Cross, Amanda J.
AU - Diergaarde, Brenda
AU - Gallinger, Steven J.
AU - Gunter, Marc J.
AU - Harlid, Sophia
AU - Hidaka, Akihisa
AU - Hoffmeister, Michael
AU - Brenner, Hermann
AU - Chang-Claude, Jenny
AU - Hsu, Li
AU - Jenkins, Mark A.
AU - Lin, Yi
AU - Milne, Roger L.
AU - Moreno, Victor
AU - Newcomb, Polly A.
AU - Nishihara, Reiko
AU - Obon-Santacana, Mireia
AU - Pai, Rish K.
AU - Sakoda, Lori C.
AU - Schoen, Robert E.
AU - Slattery, Martha L.
AU - Sun, Wei
AU - Amitay, Efrat L.
AU - Alwers, Elizabeth
AU - Thibodeau, Stephen N.
AU - Toland, Amanda E.
AU - Van Guelpen, Bethany
AU - Zaidi, Syed H.
AU - Potter, John D.
AU - Meyerhardt, Jeffrey A.
AU - Giannakis, Marios
AU - Song, Mingyang
AU - Nowak, Jonathan A.
AU - Peters, Ulrike
AU - Phipps, Amanda I.
AU - Ogino, Shuji
N1 - Funding Information: Harvard cohorts (HPFS, NHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R00 CA215314, and R35 CA197735) and NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, and R35 CA197735). Additionally, laboratories of M.G. and S.O. were supported by the Cancer Research UK Grand Challenge Award (UK C10674/A27140). Funding Information: OFCCR: The Ontario Familial Colorectal Cancer Registry was supported in part by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award U01 CA167551 and award U01/U24 CA074783 (to S.G.). Additional funding for the OFCCR and ARCTIC testing and genetic analysis was provided by Canadian Cancer Society CaRE (Cancer Risk Evaluation) program grant and Ontario Research Fund award GL201-043 (to B.W.Z.), through the Canadian Institutes of Health Research award 112,746 (to T.J.H.), and through generous support from the Ontario Ministry of Research and Innovation. OSUMC: OCCPI funding was provided by Pelotonia and HNPCC funding was provided by the NCI (CA16058 and CA67941). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6–1, BR 1704/6–3, BR 1704/6–4, CH 117/1–1, HO 5117/2–1, HE 5998/2–1, KL 2354/3–1, RO 2270/8–1 and BR 1704/17–1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). Funding Information: NSHDS: Swedish Cancer Society; Cancer Research Foundation in Northern Sweden; Swedish Research Council; J C Kempe Memorial Fund; Faculty of Medicine, Umeå University, Umeå, Sweden; and Cutting-Edge Research Grant from the County Council of Västerbotten, Sweden. Funding Information: MCCS: Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209,057, 396,414 and 1,074,383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. New South Wales (NSW) cancer registry data were obtained via the ACD with the assistance of the NSW Ministry of Health. Funding Information: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088 and R01 CA248857). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Scientific Computing Infrastructure at Fred Hutch funded by ORIP grant S10OD028685. Funding Information: The Colon Cancer Family Registry (CCFR): The Colon Cancer Family Registry (CCFR, www.coloncfr.org ) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551). The Seattle Colon Cancer Family Registry was also supported in part by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under R01 CA076366 (to P.A.N.). The content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR. Funding Information: EPIC: The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRCItaly and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232,997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14,136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1,000,143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom). Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84,968–06). Funding Information: SCCFR: The Seattle Colon Cancer Family Registry was supported in part by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under awards U01 CA167551, U01 CA074794 (to J.D.P.), and awards U24 CA074794 and R01 CA076366 (to P.A.N.). Funding Information: CCFR: The Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and the financial support from the U.S. National Cancer Institute, without which this important registry would not exist. CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. DACHS: We thank all participants and cooperating clinicians, and Ute Handte-Daub, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. EDRN: We acknowledge all the following contributors to the development of the resource: University of Pittsburgh School of Medicine, Department of Gastroenterology, Hepatology and Nutrition: Lynda Dzubinski; University of Pittsburgh School of Medicine, Department of Pathology: Michelle Bisceglia; and University of Pittsburgh School of Medicine, Department of Biomedical Informatics. EPIC: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Harvard cohorts (HPFS, NHS): The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the participants and staff of the HPFS and NHS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. NSHDS: NSHDS investigators thank the Biobank Research Unit at Umeå University, the Västerbotten Intervention Programme, the Northern Sweden MONICA study and Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). SCCFR: The authors would like to thank the study participants and staff of the Seattle Colon Cancer Family Registry and the Hormones and Colon Cancer study (CORE Studies). TCGA: The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga Funding Information: CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Funding Information: NSHDS: NSHDS investigators thank the Biobank Research Unit at Umeå University, the Västerbotten Intervention Programme, the Northern Sweden MONICA study and Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). Publisher Copyright: © 2023, Japanese Society of Gastroenterology.
PY - 2023/3
Y1 - 2023/3
N2 - Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics. Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation. Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70–0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15–3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages. Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
AB - Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics. Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation. Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70–0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15–3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages. Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
KW - Biogeography
KW - Epigenetics
KW - Mismatch repair
KW - Molecular pathological epidemiology
KW - Young-onset cancer
UR - http://www.scopus.com/inward/record.url?scp=85146393347&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85146393347&partnerID=8YFLogxK
U2 - 10.1007/s00535-023-01955-2
DO - 10.1007/s00535-023-01955-2
M3 - Article
C2 - 36648535
AN - SCOPUS:85146393347
SN - 0944-1174
VL - 58
SP - 229
EP - 245
JO - Journal of Gastroenterology
JF - Journal of Gastroenterology
IS - 3
ER -