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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.

ABSTRACT: Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0 × 10(-3) were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint?8.9 × 10(-6)), two SNPs in SLC25A21 (combined Pint?4.8 × 10(-5)), and three SNPs in PLCG2 (combined Pint?4.5 × 10(-5)). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint?2.7 × 10(-5)), one SNP in CD80 (combined Pint?8.2 × 10(-6)), three SNPs on chr17 near TMEM132E (combined Pint?2.2×10(-6)), and two SNPs on chr18 near SLC25A52 (combined Pint?4.6 × 10(-5)). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

SUBMITTER: Rudolph A

PROVIDER: S-EPMC3863710 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.

Rudolph Anja A Hein Rebecca R Lindström Sara S Beckmann Lars L Behrens Sabine S Liu Jianjun J Aschard Hugues H Bolla Manjeet K MK Wang Jean J Truong Thérèse T Cordina-Duverger Emilie E Menegaux Florence F Brüning Thomas T Harth Volker V Severi Gianluca G Baglietto Laura L Southey Melissa M Chanock Stephen J SJ Lissowska Jolanta J Figueroa Jonine D JD Eriksson Mikael M Humpreys Keith K Darabi Hatef H Olson Janet E JE Stevens Kristen N KN Vachon Celine M CM Knight Julia A JA Glendon Gord G Mulligan Anna Marie AM Ashworth Alan A Orr Nicholas N Schoemaker Minouk M Webb Penny M PM Guénel Pascal P Brauch Hiltrud H Giles Graham G García-Closas Montserrat M Czene Kamila K Chenevix-Trench Georgia G Couch Fergus J FJ Andrulis Irene L IL Swerdlow Anthony A Hunter David J DJ Flesch-Janys Dieter D Easton Douglas F DF Hall Per P Nevanlinna Heli H Kraft Peter P Chang-Claude Jenny J

Endocrine-related cancer 20131104 6

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases ( ...[more]

PMID: 24080446

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Project description:INTRODUCTION:Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density. METHODS:The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density. RESULTS:No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02). CONCLUSIONS:The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.

Project description:Muscle mass and strength reduce during ageing with a steeper decline in women around the age of 50, which suggests that the menopausal transition is one of the mechanisms for age-induced neuromuscular deteriorations. At the moment, there is no clear explanation for the decline in muscle properties although both physical exercise and maintaining near premenopausal estrogen levels by hormonal replacement have been helpful in their preservation. However, the molecular consequences of both treatments in skeletal muscle are mostly unknown. The goal of this genome-wide study was to investigate the transcriptional networks through which power training (PT) comprising of jumping activities and estrogen containing hormone replacement therapy (HRT) may aid in the prevention of functional limitation ensued from insufficient muscle mass and physical performance after menopause. We used m. vastus lateralis samples obtained from postmenopausal women participating in a yearlong randomized double-blinded placebo-controlled trial with PT and HRT interventions. Muscle samples were available from eight PT, ten HRT and nine control women. Women in the PT group participated in a progressive PT program comprising mostly of jumping exercises for lower limbs with additional resistance exercises for the upper body. HRT intervention was double-blinded. All participants used either estradiol/noretisterone acetate preparation or placebo. Using statistical threshold p-value <0.05 and |fold change| >1.2 we identified 665 genes being differentially expressed among the studied 50-57-yr-old postmenopausal women. We used the hierarchical clustering method with extensive enrichment analysis in order to reveal enrichment of known GO or KEGG functional categories among co-regulated gene-clusters. In the enrichment analysis false discovery rate was set to be less than 15%. Transcription of “response to contraction”-, “insulin signaling”- and “adipocytokine signaling”-genes were upregulated by PT. Both PT and HRT were similarly effective on transcriptional regulation of glycolytic energy metabolism and calcium signaling. The HRT specifically affected “mitochondrion”-genes. In addition, we identified functional categories, such as “muscle development”, which were changed during the trial in all study groups. Our study revealed transcriptional changes in several functional categories in thigh muscle tissue of early postmenopausal women. The results emphasize that during the first years of the postmenopausal period, muscle properties are under transcriptional modulation, which both PT and HRT partially counteract leading to preservation of muscle mass and performance. More specifically, our findings indicate that PT and HRT may function through improving energy metabolism, improving the response to contraction, preserving functionality of mitochondria and reducing reorganization of muscle tissue. Therefore these treatments are recommended for preservation of adequate muscle mass and function. 54 samples, which formed 3 study groups with 2 timepoints, i.e., 8 power training subjects, 10 hormone replacement subjects and 9 controls. 6 control subjects had replicated samples resulting in a total of 60 hybridizations.

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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.

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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.

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