Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.
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Abstract
Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.
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Acknowledgements: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCFS thank Maggie Angelakos, Judi Maskiell, Gillian Dite. ESTHER thanks Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. GENICA thanks Christian Baisch, Hans-Peter Fischer, Anne Lotz, and Beate Pesch. KARMA and SASBAC thank the Swedish Medical Research Counsel. MARIE thanks Petra Seibold, Sabine Behrens, Ursula Eilber and Muhabbet Celik. MTLGEBCS would like to thank Martine Tranchant (CHU de Québec – Université Laval Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skilful technical assistance. J.S. is Chair holder of the Canada Research Chair in Oncogenetics. NBHS thanks study participants and research staff for their contributions and commitment to the study. The OFBCR thanks Teresa Selander, Nayana Weerasooriya and Steve Gallinger. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner. SBCS thanks Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian and Malcolm W.R. Reed. We thank the SEARCH team.
Funder: Genome Canada; doi: http://dx.doi.org/10.13039/100008762
Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024
Funder: Ministère de l’Économie et de l'Innovation du Québec
Funder: Government of Canada; doi: http://dx.doi.org/10.13039/501100000023
Funder: Génome Québec; doi: http://dx.doi.org/10.13039/100013062
Funder: Fondation du cancer du sein du Québec; doi: http://dx.doi.org/10.13039/100016328
Funder: Confluence project by National Cancer Institute Intramural Research Program, National Institutes of Health
Funder: Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer
Funder: Susan G. Komen for the Cure; doi: http://dx.doi.org/10.13039/100000869
Funder: Breast Cancer Research Foundation
Funder: Ovarian Cancer Research Fund; doi: http://dx.doi.org/10.13039/100001282
Funder: National Health and Medical Research Council of Australia
Funder: Cancer Council NSW; doi: http://dx.doi.org/10.13039/501100001102
Funder: Victorian Health Promotion Foundation (Australia)
Funder: Victorian Breast Cancer Research Consortium
Funder: National Health and Medical Research Council
Funder: Fondation de France; doi: http://dx.doi.org/10.13039/501100004431
Funder: Institut National du Cancer (INCa)
Funder: Ligue Nationale contre le Cancer
Funder: Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail; doi: http://dx.doi.org/10.13039/501100007546
Funder: Agence Nationale de la Recherche
Funder: Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg; doi: http://dx.doi.org/10.13039/501100003542
Funder: Robert Bosch Stiftung; doi: http://dx.doi.org/10.13039/501100001646
Funder: Deutsches Krebsforschungszentrum; doi: http://dx.doi.org/10.13039/100008658
Funder: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)
Funder: Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany
Funder: Märit and Hans Rausings Initiative Against Breast Cancer
Funder: Hamburger Krebsgesellschaft; doi: http://dx.doi.org/10.13039/100018515
Funder: Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA
Funder: Agency for Science, Technology and Research of Singapore
Funder: US National Institute of Health
Funder: Susan G. Komen; doi: http://dx.doi.org/10.13039/100009634
Funder: Sheffield Experimental Cancer Medicine Centre
Funder: Breast Cancer Now Tissue Bank
Funder: UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
Funder: NHS in the East of England through the Clinical Academic Reserve
Funder: Ruhr-Universität Bochum (1007)
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1573-7284
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European Commission Horizon 2020 (H2020) Societal Challenges (633784)
Cancer Research UK (C1287/A8459)
National Institutes of Health (NIH) (via University of Southern California) (1 U19 CA148537-01)
National Cancer Institute (U19CA148537)
European Commission (223175)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
Cancer Research UK (10710)
Cancer Research UK (16563)
Cancer Research UK (12014)
Cancer Research UK (10118)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (16565)