Association between Smoking and Molecular Subtypes of Colorectal Cancer

Xiaoliang Wang; Efrat Amitay; Tabitha A. Harrison; Barbara L. Banbury; Sonja I. Berndt; Hermann Brenner; Daniel D. Buchanan; Peter T. Campbell; Yin Cao; Andrew T. Chan; Jenny Chang-Claude; Steven J. Gallinger; Marios Giannakis; Graham G. Giles; Marc J. Gunter; John L. Hopper; Mark A. Jenkins; Yi Lin; Victor Moreno; Reiko Nishihara; Polly A. Newcomb; Shuji Ogino; Amanda I. Phipps; Lori C. Sakoda; Robert E. Schoen; Martha L. Slattery; Mingyang Song; Wei Sun; Steven N. Thibodeau; Amanda E. Toland; Bethany Van Guelpen; Michael O. Woods; Li Hsu; Ulrike Peters

doi:10.1093/jncics/pkab056

Association between Smoking and Molecular Subtypes of Colorectal Cancer

Xiaoliang Wang, Efrat Amitay, Tabitha A. Harrison, Barbara L. Banbury, Sonja I. Berndt, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Yin Cao, Andrew T. Chan, Jenny Chang-Claude, Steven J. Gallinger, Marios Giannakis, Graham G. Giles, Marc J. Gunter, John L. Hopper, Mark A. Jenkins, Yi Lin, Victor Moreno, Reiko NishiharaPolly A. Newcomb, Shuji Ogino, Amanda I. Phipps, Lori C. Sakoda, Robert E. Schoen, Martha L. Slattery, Mingyang Song, Wei Sun, Steven N. Thibodeau, Amanda E. Toland, Bethany Van Guelpen, Michael O. Woods, Li Hsu, Ulrike Peters

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P < .trend <01). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio 1.90, 95% confidence interval 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio=1.35, 95% confidence interval 1.22 to 1.49; Pdifference 2.1 × 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (Pdifference < .001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.

Original language	English (US)
Article number	pkab056
Journal	JNCI Cancer Spectrum
Volume	5
Issue number	4
DOIs	https://doi.org/10.1093/jncics/pkab056
State	Published - Aug 1 2021
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/jncics/pkab056

Cite this

Wang, X., Amitay, E., Harrison, T. A., Banbury, B. L., Berndt, S. I., Brenner, H., Buchanan, D. D., Campbell, P. T., Cao, Y., Chan, A. T., Chang-Claude, J., Gallinger, S. J., Giannakis, M., Giles, G. G., Gunter, M. J., Hopper, J. L., Jenkins, M. A., Lin, Y., Moreno, V., ... Peters, U. (2021). Association between Smoking and Molecular Subtypes of Colorectal Cancer. JNCI Cancer Spectrum, 5(4), Article pkab056. https://doi.org/10.1093/jncics/pkab056

Wang, X, Amitay, E, Harrison, TA, Banbury, BL, Berndt, SI, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Gallinger, SJ, Giannakis, M, Giles, GG, Gunter, MJ, Hopper, JL, Jenkins, MA, Lin, Y, Moreno, V, Nishihara, R, Newcomb, PA, Ogino, S, Phipps, AI, Sakoda, LC, Schoen, RE, Slattery, ML, Song, M, Sun, W, Thibodeau, SN, Toland, AE, Van Guelpen, B, Woods, MO, Hsu, L & Peters, U 2021, 'Association between Smoking and Molecular Subtypes of Colorectal Cancer', JNCI Cancer Spectrum, vol. 5, no. 4, pkab056. https://doi.org/10.1093/jncics/pkab056

@article{43f060bd53574a7ab13da755e4e4ec45,

title = "Association between Smoking and Molecular Subtypes of Colorectal Cancer",

abstract = "Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P < .trend <01). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio 1.90, 95% confidence interval 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio=1.35, 95% confidence interval 1.22 to 1.49; Pdifference 2.1 × 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (Pdifference < .001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.",

author = "Xiaoliang Wang and Efrat Amitay and Harrison, {Tabitha A.} and Banbury, {Barbara L.} and Berndt, {Sonja I.} and Hermann Brenner and Buchanan, {Daniel D.} and Campbell, {Peter T.} and Yin Cao and Chan, {Andrew T.} and Jenny Chang-Claude and Gallinger, {Steven J.} and Marios Giannakis and Giles, {Graham G.} and Gunter, {Marc J.} and Hopper, {John L.} and Jenkins, {Mark A.} and Yi Lin and Victor Moreno and Reiko Nishihara and Newcomb, {Polly A.} and Shuji Ogino and Phipps, {Amanda I.} and Sakoda, {Lori C.} and Schoen, {Robert E.} and Slattery, {Martha L.} and Mingyang Song and Wei Sun and Thibodeau, {Steven N.} and Toland, {Amanda E.} and {Van Guelpen}, Bethany and Woods, {Michael O.} and Li Hsu and Ulrike Peters",

note = "Funding Information: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute (NCI), National Institutes of Health (NIH), US Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, U01 CA164930). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) (X01-HG008596 and X-01-HG007585). CIDR is fully funded through a federal contract from the National Institutes of Health to Johns Hopkins University, contract number HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CCFR, www.coloncfr.org ) is supported in part by funding from the NCI, NIH (award U01 CA167551). The CCFR Set-1 (Illumina 1 M/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 600 K SNP array) was supported by NIH award U19 CA148107 (to SBG) and by the CIDR, which is funded by the NIH to Johns Hopkins University, contract number HHSN268201200008I. The SCCFR Illumina HumanCytoSNP array was supported through NCI award R01 CA076366 (to PAN). 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 content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH, or any of the collaborating centers in the 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. This study was conducted with institutional review board approval. 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). DALS: National Institutes of Health (R01 CA48998 to ML Slattery). EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). 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 G{\'e}n{\'e}rale de l{\textquoteright}Education Nationale, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (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 232997 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 Andaluc{\'i}a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Sk{\aa}ne and V{\"a}sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom). Harvard cohorts (HPFS, NHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003) and NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673, and P50 CA127003). 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. NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, US Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Montr{\'e}al, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. NSHDS: Swedish Cancer Society; Cancer Research Foundation in Northern Sweden; Swedish Research Council; J C Kempe Memorial Fund; Faculty of Medicine, Ume{\aa} University, Ume{\aa}, Sweden; and Cutting-Edge Research Grant from the County Council of V{\"a}sterbotten, Sweden. OFCCR: The Ontario Familial Colorectal Cancer Registry was supported in part by the NCI/NIH under award U01 CA167551 and award U01/U24 CA074783 (to SG). Additional funding for the OFCCR and ARCTIC testing and genetic analysis was through and a Canadian Cancer Society CaRE (Cancer Risk Evaluation) program grant and Ontario Research Fund award GL201-043 (to BWZ), through the Canadian Institutes of Health Research award 112746 (to TJH), 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). SCCFR: The Seattle Colon Cancer Family Registry was supported in part by the NCI/NIH under awards U01 CA167551, U01 CA074794 (to JDP), and awards U24 CA074794 and R01 CA076366 (to PAN). Funding Information: Acknowledgements : 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 everyone who provided 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 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 (HPFS, NHS): The study protocol was approved by the institutional review boards of the Brigham and Women{\textquoteright}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 Biobank Research Unit at Ume{\aa} University, the V{\"a}sterbotten Intervention Programme, the Northern Sweden MONICA study, and Region V{\"a}sterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). Publisher Copyright: {\textcopyright} The Author(s) 2021. Published by Oxford University Press.",

year = "2021",

month = aug,

day = "1",

doi = "10.1093/jncics/pkab056",

language = "English (US)",

volume = "5",

journal = "JNCI Cancer Spectrum",

issn = "2515-5091",

publisher = "Oxford University Press",

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}

TY - JOUR

T1 - Association between Smoking and Molecular Subtypes of Colorectal Cancer

AU - Wang, Xiaoliang

AU - Amitay, Efrat

AU - Harrison, Tabitha A.

AU - Banbury, Barbara L.

AU - Berndt, Sonja I.

AU - Brenner, Hermann

AU - Buchanan, Daniel D.

AU - Campbell, Peter T.

AU - Cao, Yin

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Gallinger, Steven J.

AU - Giannakis, Marios

AU - Giles, Graham G.

AU - Gunter, Marc J.

AU - Hopper, John L.

AU - Jenkins, Mark A.

AU - Lin, Yi

AU - Moreno, Victor

AU - Nishihara, Reiko

AU - Newcomb, Polly A.

AU - Ogino, Shuji

AU - Phipps, Amanda I.

AU - Sakoda, Lori C.

AU - Schoen, Robert E.

AU - Slattery, Martha L.

AU - Song, Mingyang

AU - Sun, Wei

AU - Thibodeau, Steven N.

AU - Toland, Amanda E.

AU - Van Guelpen, Bethany

AU - Woods, Michael O.

AU - Hsu, Li

AU - Peters, Ulrike

N1 - Funding Information: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute (NCI), National Institutes of Health (NIH), US Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, U01 CA164930). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) (X01-HG008596 and X-01-HG007585). CIDR is fully funded through a federal contract from the National Institutes of Health to Johns Hopkins University, contract number HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CCFR, www.coloncfr.org ) is supported in part by funding from the NCI, NIH (award U01 CA167551). The CCFR Set-1 (Illumina 1 M/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 600 K SNP array) was supported by NIH award U19 CA148107 (to SBG) and by the CIDR, which is funded by the NIH to Johns Hopkins University, contract number HHSN268201200008I. The SCCFR Illumina HumanCytoSNP array was supported through NCI award R01 CA076366 (to PAN). 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 content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH, or any of the collaborating centers in the 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. This study was conducted with institutional review board approval. 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). DALS: National Institutes of Health (R01 CA48998 to ML Slattery). EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). 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 232997 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 (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom). Harvard cohorts (HPFS, NHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003) and NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673, and P50 CA127003). 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. NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, US Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. 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. OFCCR: The Ontario Familial Colorectal Cancer Registry was supported in part by the NCI/NIH under award U01 CA167551 and award U01/U24 CA074783 (to SG). Additional funding for the OFCCR and ARCTIC testing and genetic analysis was through and a Canadian Cancer Society CaRE (Cancer Risk Evaluation) program grant and Ontario Research Fund award GL201-043 (to BWZ), through the Canadian Institutes of Health Research award 112746 (to TJH), 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). SCCFR: The Seattle Colon Cancer Family Registry was supported in part by the NCI/NIH under awards U01 CA167551, U01 CA074794 (to JDP), and awards U24 CA074794 and R01 CA076366 (to PAN). Funding Information: Acknowledgements : 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 everyone who provided 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 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 (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 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: © The Author(s) 2021. Published by Oxford University Press.

PY - 2021/8/1

Y1 - 2021/8/1

N2 - Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P < .trend <01). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio 1.90, 95% confidence interval 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio=1.35, 95% confidence interval 1.22 to 1.49; Pdifference 2.1 × 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (Pdifference < .001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.

AB - Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P < .trend <01). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio 1.90, 95% confidence interval 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio=1.35, 95% confidence interval 1.22 to 1.49; Pdifference 2.1 × 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (Pdifference < .001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.

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DO - 10.1093/jncics/pkab056

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M1 - pkab056

ER -

Association between Smoking and Molecular Subtypes of Colorectal Cancer

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UN SDGs

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