Abstract
Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference =.03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 348-360 |
| Number of pages | 13 |
| Journal | International Journal of Cancer |
| Volume | 151 |
| Issue number | 3 |
| DOIs | |
| State | Published - Aug 1 2022 |
Keywords
- colorectal cancer
- diabetes
- subtype
ASJC Scopus subject areas
- Oncology
- Cancer Research
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In: International Journal of Cancer, Vol. 151, No. 3, 01.08.2022, p. 348-360.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Diabetes mellitus in relation to colorectal tumor molecular subtypes
T2 - A pooled analysis of more than 9000 cases
AU - Harlid, Sophia
AU - Van Guelpen, Bethany
AU - Qu, Conghui
AU - Gylling, Björn
AU - Aglago, Elom K.
AU - Amitay, Efrat L.
AU - Brenner, Hermann
AU - Buchanan, Daniel D.
AU - Campbell, Peter T.
AU - Cao, Yin
AU - Chan, Andrew T.
AU - Chang-Claude, Jenny
AU - Drew, David A.
AU - Figueiredo, Jane C.
AU - French, Amy J.
AU - Gallinger, Steven
AU - Giannakis, Marios
AU - Giles, Graham G.
AU - Gunter, Marc J.
AU - Hoffmeister, Michael
AU - Hsu, Li
AU - Jenkins, Mark A.
AU - Lin, Yi
AU - Moreno, Victor
AU - Murphy, Neil
AU - Newcomb, Polly A.
AU - Newton, Christina C.
AU - Nowak, Jonathan A.
AU - Obón-Santacana, Mireia
AU - Ogino, Shuji
AU - Potter, John D.
AU - Song, Mingyang
AU - Steinfelder, Robert S.
AU - Sun, Wei
AU - Thibodeau, Stephen N.
AU - Toland, Amanda E.
AU - Ugai, Tomotaka
AU - Um, Caroline Y.
AU - Woods, Michael O.
AU - Phipps, Amanda I.
AU - Harrison, Tabitha
AU - Peters, Ulrike
N1 - Funding Information: 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). Support for case ascertainment was provided in part from the Surveillance, Epidemiology and End Results (SEER) Program and the following U.S. state cancer registries: AZ, CO, MN, NC, NH; and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). The CCFR Set‐1 (Illumina 1M/1M‐Duo) and Set‐2 (Illumina Omni1‐Quad) scans were supported by NIH awards U01 CA122839 and R01 CA143247 (to GC). The CCFR Set‐3 (Affymetrix Axiom CORECT Set array) was supported by NIH award U19 CA148107 and R01 CA81488 (to SBG). The CCFR Set‐4 (Illumina OncoArray 600K SNP array) was supported by NIH award U19 CA148107 (to SBG) and by the Center for Inherited Disease Research (CIDR), which is funded by the NIH to the Johns Hopkins University, contract number HHSN268201200008I. Additional funding for the OFCCR/ARCTIC was through award GL201‐043 from the Ontario Research Fund (to BWZ), award 112746 from the Canadian Institutes of Health Research (to TJH), through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society (to SG) and through generous support from the Ontario Ministry of Research and Innovation. The SFCCR Illumina HumanCytoSNP array was supported in part through NCI/NIH awards U01/U24 CA074794 and R01 CA076366 (to PAN). The content of this article 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: CCFR: The Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff and the financial support from the US National Cancer Institute, without which this important registry would not exist. 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). 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 our 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 everyone who provided excellent technical assistance. 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 investigators thank the Västerbotten Intervention Programme, the Northern Sweden MONICA study, the Biobank Research Unit at Umeå Universitet and Biobanken Norr at Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council. Funding Information: EPIC: The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). 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), German Institute of Human Nutrition Potsdam‐ Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Dutch ZON (Zorg Onderzoek Nederland), Statistics Netherlands (The Netherlands), LK Research Funds, Dutch Prevention Funds, Netherlands Cancer Registry (NKR), World Cancer Research Fund (WCRF); Health Research Fund (FIS) ‐ Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra and the Catalan Institute of Oncology ‐ ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC‐Norfolk; C8221/A29017 to EPIC‐Oxford), Medical Research Council (1000143 to EPIC‐Norfolk; MR/M012190/1 to EPIC‐Oxford). (United Kingdom). Funding Information: Marios Giannakis reports potential financial conflicts of interest through research funding from Bristol‐Myers Squibb, Merck, Servier and Janssen unrelated to our study. Victor Moreno reports grants from Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723; Instituto de Salud Carlos III grant PI17‐00092; Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE, Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), action Genrisk. Jonathan Nowak reports prior research funding (for pilot projects) from NanoString and Illumina and ongoing research funding (for technology development) from Akoya Biosciences, unrelated to our study. Mireia Obón‐Santacana reports a post‐doctoral fellowship from the Spanish Association Against Cancer Scientific Foundation (AECC; POSTD037OBÓN). All other authors declare no conflicts of interest. Funding Information: Harvard cohorts (HPFS, NHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA151993, R35 CA197735 and R35 CA253185), and NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735 and R35 CA253185). 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, R01 CA059045, R01CA201407). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) contract number HHSN268201700006I and HHSN268201200008I. 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 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: CCFR: The Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff and the financial support from the US National Cancer Institute, without which this important registry would not exist. 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). 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 our 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 everyone who provided excellent technical assistance. 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 investigators thank the Västerbotten Intervention Programme, the Northern Sweden MONICA study, the Biobank Research Unit at Umeå Universitet and Biobanken Norr at Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council. Funding Information: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 396414 and 1074383 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. Publisher Copyright: © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference =.03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
AB - Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference =.03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
KW - colorectal cancer
KW - diabetes
KW - subtype
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UR - http://www.scopus.com/inward/citedby.url?scp=85129087573&partnerID=8YFLogxK
U2 - 10.1002/ijc.34015
DO - 10.1002/ijc.34015
M3 - Article
C2 - 35383926
AN - SCOPUS:85129087573
SN - 0020-7136
VL - 151
SP - 348
EP - 360
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -