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Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Published version
Peer-reviewed

Repository DOI


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Authors

Hoppe, Reiner 
Ickstadt, Katja 
Behrens, Thomas 
Winter, Stefan 

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.

Description

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)

Keywords

Circadian rhythm, MAPK8, Serotonin biosynthesis, Shift work, TPH2, Humans, Female, Breast Neoplasms, Melatonin, Bayes Theorem, Polymorphism, Single Nucleotide, Logistic Models, Case-Control Studies, Genetic Predisposition to Disease

Journal Title

Eur J Epidemiol

Conference Name

Journal ISSN

0393-2990
1573-7284

Volume Title

38

Publisher

Springer Science and Business Media LLC
Sponsorship
European Commission Horizon 2020 (H2020) Societal Challenges (634935)
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)