Abstract
Background
Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors.
Methods
Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status.
Results
The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests).
Conclusions
The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.
Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors.
Methods
Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status.
Results
The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests).
Conclusions
The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.
| Original language | English |
|---|---|
| Pages (from-to) | 526-536 |
| Number of pages | 11 |
| Journal | International Journal of Epidemiology |
| Volume | 47 |
| Issue number | 2 |
| Early online date | 05 Jan 2018 |
| DOIs | |
| Publication status | Published - Apr 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by the Intramural Research Funds of the National Cancer Institute, Cancer Research UK (C1287/A16563, C1287/A10118), the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively) and by the European Community′s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2–2009–223175) (COGS) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT: Ministry of Science and ICT) (No. 2017R1C1B1010410). The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). 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 Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is an NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007– 3839; 2009 4363). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BREast Oncology GAlician Network (BREOGAN) is funded by: FIS ISCIII/ PI12/02125 Acción Estratégica de Salud del Instituto de Salud Carlos III, FEDER; FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11–192, Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta, Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev and Gentofte Hospital. The ESTHER study was supported 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, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. 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 and by the strategic funding of the University of Eastern Finland. LMBC is supported by the ‘Stichting tegen Kanker’. D.L. is supported by the FWO. The MARIE study was supported by the Deutsche Krebshilfe e.V. (70–2892-BR I, 106332, 108253, 108419, 110826, 110828), the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation and a generous gift from the David F and Margaret T Grohne Family Foundation. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program: grant # CRN-87521, and the Ministry of Economic Development, Innovation and Export Trade: grant # PSR-SIIRI-701. MCCS cohort recruitment was funded by VicHealth
Funding Information:
and Cancer Council Victoria. The MCCS was further supported by Australian National Health and Medical Research Council grants 209057 and 396414 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G Komen Breast Cancer Foundation. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London; ICR acknowledges NHS funding to the NIHR Biomedical Research Centre.
Publisher Copyright:
© 2018, International Journal of Epidemiology.
Keywords
- Breast cancer
- Epidemiology
- Gene-environment interactions
- Genetic susceptibility
- Risk prediction
ASJC Scopus subject areas
- Epidemiology
