Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.
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Wichert Katharina, Hoppe Reiner, Ickstadt Katja, Behrens Thomas, Winter Stefan, Herold Robert, Terschüren Claudia, Lo Wing-Yee, Guénel Pascal, Truong Thérèse, Bolla Manjeet K, Wang Qin, Dennis Joe, Michailidou Kyriaki, Lush Michael, Andrulis Irene L, Brenner Hermann, Chang-Claude Jenny, Cox Angela, Cross Simon S, Czene Kamila, Eriksson Mikael, Figueroa Jonine D, García-Closas Montserrat, Goldberg Mark S, Hamann Ute, He Wei, Holleczek Bernd, Hopper John L, Jakubowska Anna, Ko Yon-Dschun, Lubiński Jan, Mulligan Anna Marie, Obi Nadia, Rhenius Valerie, Shah Mitul, Shu Xiao-Ou, Simard Jacques, Southey Melissa C, Zheng Wei, Dunning Alison M, Pharoah Paul D P, Hall Per, Easton Douglas F, Brüning Thomas, Brauch Hiltrud, Harth Volker, Rabstein Sylvia
Аннотация
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.