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ItemNo Preview AvailableGenetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction studyRudolph, A ; Hein, R ; Lindstroem, S ; Beckmann, L ; Behrens, S ; Liu, J ; Aschard, H ; Bolla, MK ; Wang, J ; Truong, T ; Cordina-Duverger, E ; Menegaux, F ; Bruening, T ; Harth, V ; Severi, G ; Baglietto, L ; Southey, M ; Chanock, SJ ; Lissowska, J ; Figueroa, JD ; Eriksson, M ; Humpreys, K ; Darabi, H ; Olson, JE ; Stevens, KN ; Vachon, CM ; Knight, JA ; Glendon, G ; Mulligan, AM ; Ashworth, A ; Orr, N ; Schoemaker, M ; Webb, PM ; Guenel, P ; Brauch, H ; Giles, G ; Garcia-Closas, M ; Czene, K ; Chenevix-Trench, G ; Couch, FJ ; Andrulis, IL ; Swerdlow, A ; Hunter, DJ ; Flesch-Janys, D ; Easton, DF ; Hall, P ; Nevanlinna, H ; Kraft, P ; Chang-Claude, J (BIOSCIENTIFICA LTD, 2013-12-01)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.
ItemUptake of offer to receive genetic information about BRCA1 and BRCA2 mutations in an Australian population-based studyKeogh, Louise A. ; Southey, Melissa C. ; Maskiell, Judi ; Young, Mary-Anne ; Gaff, Clara L. ; Kirk, Judy ; Tucker, Katherine M. ; Rosenthal, Doreen ; McCredie, Margaret R. E. ; Giles, Graham G. ; Hopper, John L. (American Association for Cancer Research, 2004)Research on the utilization of genetic testing services for mutations in BRCA1 and BRCA2 has focused on women with a strong family history of breast and ovarian cancer. We conducted a population-based case-control-family study of Australian women diagnosed with invasive breast cancer before age 40 years, unselected for family history, and tested for germ line mutations in BRCA1 and BRCA2. Case subjects found to carry a deleterious mutation and their relatives who had given a research blood sample were informed by mail that the study had identified “genetic information” and were offered the opportunity to learn more. Those interested were referred to a government-funded family cancer clinic. Of 94 subjects who received the letter, 3 (3%) did not respond and 38 (40%) declined to learn their result (16 declined the referral, 10 accepted but did not attend a clinic, and 12 attended a clinic but declined testing), and 12 (13%) remain “on hold”. The remaining 41 (44%) chose to learn their result (3 of whom already knew their mutation status). There was no evidence that the decision to learn of mutation status depended on age, gender, family history, or having been diagnosed with breast cancer. Of 19 families with more than one participant, in 11 (58%) there was discordance between relatives in receiving genetic results.