Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses

Nikos Papadimitriou*, Conghui Qu, Tabitha A Harrison, Alaina M. Bever, Richard M Martin, Konstantinos K. Tsilidis

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Background
Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain.

Methods
We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO).

Findings
A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03).

Interpretation
Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4).

Funding
Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion’s Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Original languageEnglish
Article number105010
JournalEBioMedicine
Volume101
Early online date12 Feb 2024
DOIs
Publication statusPublished - 1 Mar 2024

Bibliographical note

Funding Information:
MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria . The MCCS was further supported by Australian NHMRC grants 509348 , 209057 , 251553 and 504711 and by infrastructure provided by Cancer Council Victoria . Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database.

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 , 01ER1505B , and 01KD2104A ).

Funding Information:
CPS-II: The authors express sincere appreciation to all Cancer Prevention Study-II participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries and cancer registries supported by the National Cancer Institute's Surveillance Epidemiology and End Results Program . The authors assume full responsibility for all analyses and interpretation of results. The views expressed here are those of the authors and do not necessarily represent the American Cancer Society or the American Cancer Society—Cancer Action Network.

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). EPIC Sweden is supported by Swedish Cancer Society , Swedish Research Council and Region Skåne and Region Västerbotten (Sweden).

Funding Information:
This study was supported by Cancer Research UK ( C18281/A29019 ) and Cancer Research UK ( PPRCPJT\100005 ; Dr Tsilidis). RMM is a National Institute for Health Research Senior Investigator ( NIHR202411 ). RMM is supported by a Cancer Research UK 25 ( C18281/A29019 ) programme grant (the Integrative Cancer Epidemiology Programme). RMM is also supported by the NIHR Bristol Biomedical Research Centre which is funded by the NIHR ( BRC-1215-20011 ) and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol . RMM is affiliated with the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council ( MC_UU_00011/1 , MC_UU_00011/3 , MC_UU_00011/6 , and MC_UU_00011/4 ) and the University of Bristol . AB has received support from the National Cancer Institute ( F30CA265012 ). SO has received a grant from National Institutes of Health . TU has received support from National Institutes of Health / National Cancer Institute ( R50CA274122 ), American Institute for Cancer Research Investigator-Initiated Research Grant, Brigham and Women's Hospital Faculty Career Development Award, and Prevent Cancer Foundation Grant. BML has received support from the Victorian Cancer Agency ( MCRF18005 ). BVG has received support from Swedish Research Council , Swedish Cancer Society , Region Västerbotten , Knut and Alice Wallenberg Foundation , Lion’s Cancer Research Foundation and, Insamlingsstiftelsen , Umeå University . AET has received an R01 National Institutes of Health / National Cancer Institute funding. SB has received support from National Cancer Institute, NIH . DAD has received grants from the National Institutes of Health .

Funding Information:
Harvard cohorts: HPFS is supported by the National Institutes of Health ( P01 CA055075 , UM1 CA167552 , U01 CA167552 , R01 CA137178 , R01 CA151993 , and R35 CA197735 ), NHS by the National Institutes of Health ( P01 CA087969 , UM1 CA186107 , R01 CA137178 , R01 CA151993 , and R35 CA197735 ).

Funding Information:
NSHDS investigators thank the Västerbotten Intervention Programme, the Northern Sweden MONICA study, the Biobank Research Unit at Umeå University 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:
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. 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).

Funding Information:
EDRN: This work is funded and supported by the NCI , EDRN Grant ( U01-CA152753 ).

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 CA143237 (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 Foundation (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 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:
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 , U01 CA164930 , R21 CA191312 , R01 CA244588 , R01 CA201407 ). 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:
NSHDS: The research was supported by Biobank Sweden through funding from the Swedish Research Council ( VR 2017-00650 , VR 2017-01737 ), the Swedish Cancer Society ( CAN 2017/581 ), Region Västerbotten ( VLL-841671 , VLL-833291 ), Knut and Alice Wallenberg Foundation ( VLL-765961 ), and the Lion’s Cancer Research Foundation (several grants) and Insamlingsstiftelsen , both at Umeå University .

Funding Information:
Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.This study was supported by Cancer Research UK (C18281/A29019) and Cancer Research UK (PPRCPJT\100005; Dr Tsilidis). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). RMM is supported by a Cancer Research UK 25 (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is also supported by the NIHR Bristol Biomedical Research Centre which is funded by the NIHR (BRC-1215-20011) and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. RMM is affiliated with the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4) and the University of Bristol. AB has received support from the National Cancer Institute (F30CA265012). SO has received a grant from National Institutes of Health. TU has received support from National Institutes of Health/National Cancer Institute (R50CA274122), American Institute for Cancer Research Investigator-Initiated Research Grant, Brigham and Women's Hospital Faculty Career Development Award, and Prevent Cancer Foundation Grant. BML has received support from the Victorian Cancer Agency (MCRF18005). BVG has received support from Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation and, Insamlingsstiftelsen, Umeå University. AET has received an R01 National Institutes of Health/National Cancer Institute funding. SB has received support from National Cancer Institute, NIH. DAD has received grants from the National Institutes of Health. 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, U01 CA164930, R21 CA191312, R01 CA244588, R01 CA201407). 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. 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 CA143237 (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 Foundation (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 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. CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort. The study protocol was approved by the institutional review boards of Emory University, and those of participating registries as required. 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, 01ER1505B, and 01KD2104A). DALS: National Institutes of Health (R01 CA048998 to M. L. Slattery). EDRN: This work is funded and supported by the NCI, EDRN Grant (U01-CA152753). 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). EPIC Sweden is supported by Swedish Cancer Society, Swedish Research Council and Region Skåne and Region Västerbotten (Sweden). Harvard cohorts: HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, and R35 CA197735), NHS by the National Institutes of Health (P01 CA087969, UM1 CA186107, R01 CA137178, R01 CA151993, and R35 CA197735). MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. NSHDS: The research was supported by Biobank Sweden through funding from the Swedish Research Council (VR 2017-00650, VR 2017-01737), the Swedish Cancer Society (CAN 2017/581), Region Västerbotten (VLL-841671, VLL-833291), Knut and Alice Wallenberg Foundation (VLL-765961), and the Lion's Cancer Research Foundation (several grants) and Insamlingsstiftelsen, both at Umeå University. 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. 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 express sincere appreciation to all Cancer Prevention Study-II participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries and cancer registries supported by the National Cancer Institute's Surveillance Epidemiology and End Results Program. The authors assume full responsibility for all analyses and interpretation of results. The views expressed here are those of the authors and do not necessarily represent the American Cancer Society or the American Cancer Society—Cancer Action Network. DACHS: We thank all participants and cooperating clinicians, and everyone who provided excellent technical assistance. EDRN: We acknowledge all contributors to the development of the resource at University of Pittsburgh School of Medicine, Department of Gastroenterology, Department of Pathology, Hepatology and Nutrition and 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: 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 acknowledge Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital as home of the NHS. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and/or the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. 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 University and Biobanken Norr at Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council. Disclaimer: 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. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

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Structured keywords

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