PLOS Genetics: Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors
Research Article
Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors
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Abstract
Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 1.45="" 1p11.2-rs11249433="" additionally="" and="" being="" between="" day.="" day="" drank="" ever="" found="" g="" in="" interaction="" parous="" sub="" those="" was="" who="">interactionAuthor Summary
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2, account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1 differs with the number of births and that the risk associated with a CASP8 variant is altered by high alcohol consumption. The effect of an additional genetic variant might also be modified by reproductive factors. This knowledge will stimulate new research towards a better understanding of breast cancer development.
Citation: Nickels S, Truong T, Hein R, Stevens K, Buck K, et al. (2013) Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors. PLoS Genet 9(3): e1003284. doi:10.1371/journal.pgen.1003284
Editor: Marshall S. Horwitz, University of Washington, United States of America
Received: September 17, 2012; Accepted: December 13, 2012; Published: March 27, 2013
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme [BM0606]. DF Easton is a Principal Research Fellow of CR-UK. RL Milne is supported by Fondo de Investigación Sanitario (PI11/00923). The Australian Breast Cancer Family Registry (ABCFR; 1992-1995) was supported by the Australian NHMRC, the New South Wales Cancer Council, and the Victorian Health Promotion Foundation (Australia). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health, under RFA # CA-06-503, and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (U01 CA69417), University of Melbourne (U01 CA69638), and Georgetown University Medical Center Informatics Support Center (HHSN261200900010C). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating BCFR centres, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR. JL Hopper is an Australia Fellow and MC Southey is a Senior Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia. MC Southey and JL Hopper are Group Leaders of the Victorian Breast Cancer Research Consortium. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital. The CTS was supported by the California Breast Cancer Act of 1993, National Institutes of Health (grants R01 CA77398 and the Lon V Smith Foundation [LVS39420]), and the California Breast Cancer Research Fund (contract 97-10500). Collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ESTHER study was supportd by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114; the Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and genotyping in part by the state of Baden-Württemberg through the Medical Faculty of the University of Ulm [P.685]. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation; the NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC [145684, 288704, 454508]. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC [199600]. AB Spurdle is supported by an NHMRC Senior Research Fellowship. LMBC is supported by the “Stichting tegen Kanker” (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center, and genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. The MCBCS was supported by the NIH grants [CA122340, CA128978] and a Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The Singapore and Swedish Breast Cancer Study (SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR); the U.S. National Institute of Health (NIH); the Susan G. Komen Breast Cancer Foundation; and Märit and Hans Rausings Initiative Against Breast Cancer. The SBCS was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. SEARCH is funded by grants from Cancer Research UK [C490/A6187, C490/A10119, C490/A10124] and the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The US3SS study was supported by Massachusetts (KME, R01CA47305), Wisconsin (PAN, R01 CA47147), and New Hampshire (LT-E, R01CA69664) centers and by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT study was funded by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Editor: Marshall S. Horwitz, University of Washington, United States of America
Received: September 17, 2012; Accepted: December 13, 2012; Published: March 27, 2013
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme [BM0606]. DF Easton is a Principal Research Fellow of CR-UK. RL Milne is supported by Fondo de Investigación Sanitario (PI11/00923). The Australian Breast Cancer Family Registry (ABCFR; 1992-1995) was supported by the Australian NHMRC, the New South Wales Cancer Council, and the Victorian Health Promotion Foundation (Australia). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health, under RFA # CA-06-503, and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (U01 CA69417), University of Melbourne (U01 CA69638), and Georgetown University Medical Center Informatics Support Center (HHSN261200900010C). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating BCFR centres, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR. JL Hopper is an Australia Fellow and MC Southey is a Senior Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia. MC Southey and JL Hopper are Group Leaders of the Victorian Breast Cancer Research Consortium. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital. The CTS was supported by the California Breast Cancer Act of 1993, National Institutes of Health (grants R01 CA77398 and the Lon V Smith Foundation [LVS39420]), and the California Breast Cancer Research Fund (contract 97-10500). Collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ESTHER study was supportd by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114; the Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and genotyping in part by the state of Baden-Württemberg through the Medical Faculty of the University of Ulm [P.685]. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation; the NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC [145684, 288704, 454508]. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC [199600]. AB Spurdle is supported by an NHMRC Senior Research Fellowship. LMBC is supported by the “Stichting tegen Kanker” (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center, and genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. The MCBCS was supported by the NIH grants [CA122340, CA128978] and a Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The Singapore and Swedish Breast Cancer Study (SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR); the U.S. National Institute of Health (NIH); the Susan G. Komen Breast Cancer Foundation; and Märit and Hans Rausings Initiative Against Breast Cancer. The SBCS was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. SEARCH is funded by grants from Cancer Research UK [C490/A6187, C490/A10119, C490/A10124] and the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The US3SS study was supported by Massachusetts (KME, R01CA47305), Wisconsin (PAN, R01 CA47147), and New Hampshire (LT-E, R01CA69664) centers and by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT study was funded by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
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