CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

Xabier Garcia-Albeniz; Anja Rudolph; Carolyn Hutter; Emily White; Yi Lin; Stephanie A. Rosse; Jane C. Figueiredo; Tabitha A. Harrison; Shuo Jiao; Hermann Brenner; Graham Casey; Thomas J. Hudson; Mark Thornquist; Loic Le Marchand; John Potter; Martha L. Slattery; Brent Zanke; John A. Baron; Bette J. Caan; Stephen J. Chanock; Sonja I. Berndt; Deanna Stelling; Charles S. Fuchs; Michael Hoffmeister; Katja Butterbach; Mengmeng Du; W. James Gauderman; Marc J. Gunter; Mathieu Lemire; Shuji Ogino; Jennifer Lin; Richard B. Hayes; Robert W. Haile; Robert E. Schoen; Greg S. Warnick; Mark A. Jenkins; Stephen N. Thibodeau; Fredrick R. Schumacher; Noralane M. Lindor; Laurence N. Kolonel; John L. Hopper; Jian Gong; Daniela Seminara; Bethann M. Pflugeisen; Cornelia M. Ulrich; Conghui Qu; David Duggan; Michelle Cotterchio; Peter T. Campbell; Christopher S. Carlson; Polly A. Newcomb; Edward Giovannucci; Li Hsu; Andrew T. Chan; Ulrike Peters; Jenny Chang-Claude

doi:10.1038/bjc.2015.443

CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

Xabier Garcia-Albeniz, Anja Rudolph, Carolyn Hutter, Emily White, Yi Lin, Stephanie A. Rosse, Jane C. Figueiredo, Tabitha A. Harrison, Shuo Jiao, Hermann Brenner, Graham Casey, Thomas J. Hudson, Mark Thornquist, Loic Le Marchand, John Potter, Martha L. Slattery, Brent Zanke, John A. Baron, Bette J. Caan, Stephen J. ChanockSonja I. Berndt, Deanna Stelling, Charles S. Fuchs, Michael Hoffmeister, Katja Butterbach, Mengmeng Du, W. James Gauderman, Marc J. Gunter, Mathieu Lemire, Shuji Ogino, Jennifer Lin, Richard B. Hayes, Robert W. Haile, Robert E. Schoen, Greg S. Warnick, Mark A. Jenkins, Stephen N. Thibodeau, Fredrick R. Schumacher, Noralane M. Lindor, Laurence N. Kolonel, John L. Hopper, Jian Gong, Daniela Seminara, Bethann M. Pflugeisen, Cornelia M. Ulrich, Conghui Qu, David Duggan, Michelle Cotterchio, Peter T. Campbell, Christopher S. Carlson, Polly A. Newcomb, Edward Giovannucci, Li Hsu, Andrew T. Chan, Ulrike Peters, Jenny Chang-Claude

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

16 Scopus citations

Abstract

Background:Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.Methods:We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test.Results:The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10 -9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10 -5 (alpha threshold=3.1 × 10 -4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively.Conclusions:Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

Original language	English (US)
Pages (from-to)	221-229
Number of pages	9
Journal	British journal of cancer
Volume	114
Issue number	2
DOIs	https://doi.org/10.1038/bjc.2015.443
State	Published - Jan 19 2016

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1038/bjc.2015.443

Cite this

Garcia-Albeniz, X., Rudolph, A., Hutter, C., White, E., Lin, Y., Rosse, S. A., Figueiredo, J. C., Harrison, T. A., Jiao, S., Brenner, H., Casey, G., Hudson, T. J., Thornquist, M., Le Marchand, L., Potter, J., Slattery, M. L., Zanke, B., Baron, J. A., Caan, B. J., ... Chang-Claude, J. (2016). CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk. British journal of cancer, 114(2), 221-229. https://doi.org/10.1038/bjc.2015.443

Garcia-Albeniz, X, Rudolph, A, Hutter, C, White, E, Lin, Y, Rosse, SA, Figueiredo, JC, Harrison, TA, Jiao, S, Brenner, H, Casey, G, Hudson, TJ, Thornquist, M, Le Marchand, L, Potter, J, Slattery, ML, Zanke, B, Baron, JA, Caan, BJ, Chanock, SJ, Berndt, SI, Stelling, D, Fuchs, CS, Hoffmeister, M, Butterbach, K, Du, M, James Gauderman, W, Gunter, MJ, Lemire, M, Ogino, S, Lin, J, Hayes, RB, Haile, RW, Schoen, RE, Warnick, GS, Jenkins, MA, Thibodeau, SN, Schumacher, FR, Lindor, NM, Kolonel, LN, Hopper, JL, Gong, J, Seminara, D, Pflugeisen, BM, Ulrich, CM, Qu, C, Duggan, D, Cotterchio, M, Campbell, PT, Carlson, CS, Newcomb, PA, Giovannucci, E, Hsu, L, Chan, AT, Peters, U & Chang-Claude, J 2016, 'CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk', British journal of cancer, vol. 114, no. 2, pp. 221-229. https://doi.org/10.1038/bjc.2015.443

@article{6504b8e057f84d9799c8fc99468fd251,

title = "CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk",

abstract = "Background:Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.Methods:We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test.Results:The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10 -9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10 -5 (alpha threshold=3.1 × 10 -4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively.Conclusions:Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.",

author = "Xabier Garcia-Albeniz and Anja Rudolph and Carolyn Hutter and Emily White and Yi Lin and Rosse, {Stephanie A.} and Figueiredo, {Jane C.} and Harrison, {Tabitha A.} and Shuo Jiao and Hermann Brenner and Graham Casey and Hudson, {Thomas J.} and Mark Thornquist and {Le Marchand}, Loic and John Potter and Slattery, {Martha L.} and Brent Zanke and Baron, {John A.} and Caan, {Bette J.} and Chanock, {Stephen J.} and Berndt, {Sonja I.} and Deanna Stelling and Fuchs, {Charles S.} and Michael Hoffmeister and Katja Butterbach and Mengmeng Du and {James Gauderman}, W. and Gunter, {Marc J.} and Mathieu Lemire and Shuji Ogino and Jennifer Lin and Hayes, {Richard B.} and Haile, {Robert W.} and Schoen, {Robert E.} and Warnick, {Greg S.} and Jenkins, {Mark A.} and Thibodeau, {Stephen N.} and Schumacher, {Fredrick R.} and Lindor, {Noralane M.} and Kolonel, {Laurence N.} and Hopper, {John L.} and Jian Gong and Daniela Seminara and Pflugeisen, {Bethann M.} and Ulrich, {Cornelia M.} and Conghui Qu and David Duggan and Michelle Cotterchio and Campbell, {Peter T.} and Carlson, {Christopher S.} and Newcomb, {Polly A.} and Edward Giovannucci and Li Hsu and Chan, {Andrew T.} and Ulrike Peters and Jenny Chang-Claude",

note = "Funding Information: DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. GECCO: we would like to thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. NHS: we would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS under the supervision of Dr Immaculata Devivo and Dr David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS. We would like to thank the participants and staff of the Nurses'' Health Study 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 and WY. PLCO: we thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute; the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial; Mr Tom Riley and staff, Information Management Services, Inc.; Ms Barbara O''Brien and staff, Westat, Inc.; and Drs Bill Kopp, Wen Shao and staff, SAICFrederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. PMH: we would like to thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the programme possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. Funding details are as follows: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045). Mengmeng Du is supported by grants R25 CA094880 and P30 CA008748 from NCI. CCFR: National Institutes of Health (RFA # CA-95-011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome-wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. The following Colon CFR centres contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to MLS); NHS is supported by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. TJH and BZ are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan) and the Lung Cancer and Smoking study. The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www. ncbi.nlm.nih.gov/gap) through accession number phs000093 v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (R01 CA076366 to PAN). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201 100046C, HHSN268201100001C, HHSN268201100002C, HHSN2 68201100003C, HHSN268201100004C and HHSN271201100004C. XG-A is a recipient of an ASISA Fellowship and SEOM (Sociedad Espa{\~n}ola de Oncolog{\'i}a M{\'e}dica) grant. ATC is a Damon Runyon Clinical Investigator and is also supported by NIDDK K24DK098311. WJG is supported by grant #HL115606. SO is supported by grant R35 CA197735. Funding Information: DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhab-bet Celik and Ursula Eilber for excellent technical assistance. GECCO: we would like to thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. NHS: we would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS under the supervision of Dr Immaculata Devivo and Dr David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS. We would like to thank the participants and staff of the Nurses{\textquoteright} Health Study 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 and WY. PLCO: we thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute; the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial; Mr Tom Riley and staff, Information Management Services, Inc.; Ms Barbara O{\textquoteright}Brien and staff, Westat, Inc.; and Drs Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. PMH: we would like to thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the programme possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/ Documents%20%20Write%20a%20Paper/WHI%20Investigator% 20Short%20List.pdf. Funding details are as follows: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045). Mengmeng Du is supported by grants R25 CA094880 and P30 CA008748 from NCI. CCFR: National Institutes of Health (RFA # CA-95–011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome-wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. The following Colon CFR centres contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6–1, BR 1704/6–3, BR 1704/6–4 and CH 117/1–1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to MLS); NHS is supported by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. TJH and BZ are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan) and the Lung Cancer and Smoking study. The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www. ncbi.nlm.nih.gov/gap) through accession number phs000093 v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (R01 CA076366 to PAN). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201 100046C, HHSN268201100001C, HHSN268201100002C, HHSN2 68201100003C, HHSN268201100004C and HHSN271201100004C. XG-A is a recipient of an ASISA Fellowship and SEOM (Sociedad Espa{\~n}ola de Oncolog{\'i}a M{\'e}dica) grant. ATC is a Damon Runyon Clinical Investigator and is also supported by NIDDK K24DK098311. WJG is supported by grant #HL115606. SO is supported by grant R35 CA197735. Publisher Copyright: {\textcopyright} 2016 Cancer Research UK.",

year = "2016",

month = jan,

day = "19",

doi = "10.1038/bjc.2015.443",

language = "English (US)",

volume = "114",

pages = "221--229",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

AU - Garcia-Albeniz, Xabier

AU - Rudolph, Anja

AU - Hutter, Carolyn

AU - White, Emily

AU - Lin, Yi

AU - Rosse, Stephanie A.

AU - Figueiredo, Jane C.

AU - Harrison, Tabitha A.

AU - Jiao, Shuo

AU - Brenner, Hermann

AU - Casey, Graham

AU - Hudson, Thomas J.

AU - Thornquist, Mark

AU - Le Marchand, Loic

AU - Potter, John

AU - Slattery, Martha L.

AU - Zanke, Brent

AU - Baron, John A.

AU - Caan, Bette J.

AU - Chanock, Stephen J.

AU - Berndt, Sonja I.

AU - Stelling, Deanna

AU - Fuchs, Charles S.

AU - Hoffmeister, Michael

AU - Butterbach, Katja

AU - Du, Mengmeng

AU - James Gauderman, W.

AU - Gunter, Marc J.

AU - Lemire, Mathieu

AU - Ogino, Shuji

AU - Lin, Jennifer

AU - Hayes, Richard B.

AU - Haile, Robert W.

AU - Schoen, Robert E.

AU - Warnick, Greg S.

AU - Jenkins, Mark A.

AU - Thibodeau, Stephen N.

AU - Schumacher, Fredrick R.

AU - Lindor, Noralane M.

AU - Kolonel, Laurence N.

AU - Hopper, John L.

AU - Gong, Jian

AU - Seminara, Daniela

AU - Pflugeisen, Bethann M.

AU - Ulrich, Cornelia M.

AU - Qu, Conghui

AU - Duggan, David

AU - Cotterchio, Michelle

AU - Campbell, Peter T.

AU - Carlson, Christopher S.

AU - Newcomb, Polly A.

AU - Giovannucci, Edward

AU - Hsu, Li

AU - Chan, Andrew T.

AU - Peters, Ulrike

AU - Chang-Claude, Jenny

N1 - Funding Information: DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. GECCO: we would like to thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. NHS: we would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS under the supervision of Dr Immaculata Devivo and Dr David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS. We would like to thank the participants and staff of the Nurses'' Health Study 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 and WY. PLCO: we thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute; the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial; Mr Tom Riley and staff, Information Management Services, Inc.; Ms Barbara O''Brien and staff, Westat, Inc.; and Drs Bill Kopp, Wen Shao and staff, SAICFrederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. PMH: we would like to thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the programme possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. Funding details are as follows: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045). Mengmeng Du is supported by grants R25 CA094880 and P30 CA008748 from NCI. CCFR: National Institutes of Health (RFA # CA-95-011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome-wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. The following Colon CFR centres contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to MLS); NHS is supported by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. TJH and BZ are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan) and the Lung Cancer and Smoking study. The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www. ncbi.nlm.nih.gov/gap) through accession number phs000093 v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (R01 CA076366 to PAN). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201 100046C, HHSN268201100001C, HHSN268201100002C, HHSN2 68201100003C, HHSN268201100004C and HHSN271201100004C. XG-A is a recipient of an ASISA Fellowship and SEOM (Sociedad Española de Oncología Médica) grant. ATC is a Damon Runyon Clinical Investigator and is also supported by NIDDK K24DK098311. WJG is supported by grant #HL115606. SO is supported by grant R35 CA197735. Funding Information: DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhab-bet Celik and Ursula Eilber for excellent technical assistance. GECCO: we would like to thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. NHS: we would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS under the supervision of Dr Immaculata Devivo and Dr David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS. We would like to thank the participants and staff of the Nurses’ Health Study 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 and WY. PLCO: we thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute; the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial; Mr Tom Riley and staff, Information Management Services, Inc.; Ms Barbara O’Brien and staff, Westat, Inc.; and Drs Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. PMH: we would like to thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the programme possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/ Documents%20%20Write%20a%20Paper/WHI%20Investigator% 20Short%20List.pdf. Funding details are as follows: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045). Mengmeng Du is supported by grants R25 CA094880 and P30 CA008748 from NCI. CCFR: National Institutes of Health (RFA # CA-95–011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome-wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. The following Colon CFR centres contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6–1, BR 1704/6–3, BR 1704/6–4 and CH 117/1–1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to MLS); NHS is supported by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. TJH and BZ are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan) and the Lung Cancer and Smoking study. The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www. ncbi.nlm.nih.gov/gap) through accession number phs000093 v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (R01 CA076366 to PAN). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201 100046C, HHSN268201100001C, HHSN268201100002C, HHSN2 68201100003C, HHSN268201100004C and HHSN271201100004C. XG-A is a recipient of an ASISA Fellowship and SEOM (Sociedad Española de Oncología Médica) grant. ATC is a Damon Runyon Clinical Investigator and is also supported by NIDDK K24DK098311. WJG is supported by grant #HL115606. SO is supported by grant R35 CA197735. Publisher Copyright: © 2016 Cancer Research UK.

PY - 2016/1/19

Y1 - 2016/1/19

N2 - Background:Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.Methods:We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test.Results:The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10 -9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10 -5 (alpha threshold=3.1 × 10 -4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively.Conclusions:Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

AB - Background:Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.Methods:We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test.Results:The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10 -9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10 -5 (alpha threshold=3.1 × 10 -4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively.Conclusions:Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=84955215661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955215661&partnerID=8YFLogxK

U2 - 10.1038/bjc.2015.443

DO - 10.1038/bjc.2015.443

M3 - Article

C2 - 26766742

AN - SCOPUS:84955215661

SN - 0007-0920

VL - 114

SP - 221

EP - 229

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 2

ER -

CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

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