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

Katharina Wichert¹, Reiner Hoppe^{2

3}, Katja Ickstadt⁴, Thomas Behrens⁵, Stefan Winter^{2

3}, Robert Herold⁶, Claudia Terschüren⁶, Wing-Yee Lo⁷, Pascal Guénel⁸, Thérèse Truong⁸, Manjeet K Bolla⁹, Qin Wang⁹, Joe Dennis⁹, Kyriaki Michailidou^{9

10

11}, Michael Lush⁹, Irene L Andrulis^{12

13}, Hermann Brenner^{14

15

16}, Jenny Chang-Claude^{17

18}, Angela Cox¹⁹, Simon S Cross²⁰, Kamila Czene²¹, Mikael Eriksson²¹, Jonine D Figueroa^{22

23

24}, Montserrat García-Closas²⁴, Mark S Goldberg^{25

26}, Ute Hamann²⁷, Wei He²¹, Bernd Holleczek²⁸, John L Hopper²⁹, Anna Jakubowska^{30

31}, Yon-Dschun Ko³², Jan Lubiński³⁰, Anna Marie Mulligan^{33

34}, Nadia Obi³⁵, Valerie Rhenius³⁶, Mitul Shah³⁶, Xiao-Ou Shu³⁷, Jacques Simard³⁸, Melissa C Southey^{39

40

41}, Wei Zheng³⁷, Alison M Dunning³⁶, Paul D P Pharoah^{9

36}, Per Hall^{21

42}, Douglas F Easton^{9

36}, Thomas Brüning⁵, Hiltrud Brauch^{2

3

43

44}, Volker Harth⁶, Sylvia Rabstein⁵

Affiliations

¹ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany. katharina.wichert@dguv.de.
² Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
³ University of Tübingen, Tübingen, Germany.
⁴ Department of Statistics, TU Dortmund University, Dortmund, Germany.
⁵ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany.
⁶ Institute for Occupational and Maritime Medicine Hamburg (ZfAM), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
⁷ Department of Clinical Pathology, University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Melbourne, Melbourne, VIC, Australia.
⁸ Team "Exposome and Heredity", CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁰ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
¹¹ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
¹² Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁶ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁸ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
²⁰ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
²¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²² Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
²³ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
²⁴ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²⁵ Department of Medicine, McGill University, Montréal, QC, Canada.
²⁶ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
²⁷ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ Saarland Cancer Registry, Saarbrücken, Germany.
²⁹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
³⁰ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
³¹ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
³² Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany.
³³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³⁴ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
³⁵ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³⁶ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁷ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
³⁸ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
³⁹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁴⁰ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
⁴¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
⁴² Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁴³ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
⁴⁴ German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.

PMID: 37789226
PMCID: PMC10570222
DOI: 10.1007/s10654-023-01048-7

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

Katharina Wichert et al. Eur J Epidemiol. 2023 Oct.

. 2023 Oct;38(10):1053-1068.

doi: 10.1007/s10654-023-01048-7. Epub 2023 Oct 3.

Authors

Affiliations

¹ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany. katharina.wichert@dguv.de.
² Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
³ University of Tübingen, Tübingen, Germany.
⁴ Department of Statistics, TU Dortmund University, Dortmund, Germany.
⁵ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany.
⁶ Institute for Occupational and Maritime Medicine Hamburg (ZfAM), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
⁷ Department of Clinical Pathology, University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Melbourne, Melbourne, VIC, Australia.
⁸ Team "Exposome and Heredity", CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁰ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
¹¹ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
¹² Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁶ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁸ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
²⁰ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
²¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²² Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
²³ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
²⁴ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²⁵ Department of Medicine, McGill University, Montréal, QC, Canada.
²⁶ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
²⁷ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ Saarland Cancer Registry, Saarbrücken, Germany.
²⁹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
³⁰ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
³¹ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
³² Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany.
³³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³⁴ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
³⁵ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³⁶ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁷ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
³⁸ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
³⁹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁴⁰ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
⁴¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
⁴² Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁴³ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
⁴⁴ German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.

PMID: 37789226
PMCID: PMC10570222
DOI: 10.1007/s10654-023-01048-7

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. rs1386483_R ∧ rs1473473_D ∧ rs3729931_D: 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.

Keywords: Circadian rhythm; MAPK8; Serotonin biosynthesis; Shift work; TPH2.

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Conflict of interest statement

Hermann Brenner is a member of the Editorial Board. Otherwise, the authors report no conflicts of interest.

Figures

**Fig. 1**
Flow chart of BCAC data set for the inclusion of case-control studies in the analysis, detailed information on individual studies is provided in Suppl. table S1

See this image and copyright information in PMC

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

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

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Conflict of interest statement

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