A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication
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A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication. / Hein, Rebecca; Flesch-Janys, Dieter; Dahmen, Norbert; Beckmann, Lars; Lindström, Sara; Schoof, Nils; Czene, Kamila; Mittelstraß, Kirstin; Illig, Thomas; Seibold, Petra; Behrens, Sabine; Humphreys, Keith; Li, Jingmei; Liu, Jianjun; Olson, Janet E; Wang, Xianshu; Hankinson, Susan E; Truong, Thérèse; Menegaux, Florence; Dos Santos Silva, Isabel; Johnson, Nichola; Chen, Shou-Tung; Yu, Jyh-Cherng; Ziogas, Argyrios; Kataja, Vesa; Kosma, Veli-Matti; Mannermaa, Arto; Anton-Culver, Hoda; Shen, Chen-Yang; Brauch, Hiltrud; Peto, Julian; Guénel, Pascal; Kraft, Peter; Couch, Fergus J; Easton, Douglas F; Hall, Per; Chang-Claude, Jenny; GENICA Network.
in: BREAST CANCER RES TR, Jahrgang 138, Nr. 2, 01.04.2013, S. 529-42.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication
AU - Hein, Rebecca
AU - Flesch-Janys, Dieter
AU - Dahmen, Norbert
AU - Beckmann, Lars
AU - Lindström, Sara
AU - Schoof, Nils
AU - Czene, Kamila
AU - Mittelstraß, Kirstin
AU - Illig, Thomas
AU - Seibold, Petra
AU - Behrens, Sabine
AU - Humphreys, Keith
AU - Li, Jingmei
AU - Liu, Jianjun
AU - Olson, Janet E
AU - Wang, Xianshu
AU - Hankinson, Susan E
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Dos Santos Silva, Isabel
AU - Johnson, Nichola
AU - Chen, Shou-Tung
AU - Yu, Jyh-Cherng
AU - Ziogas, Argyrios
AU - Kataja, Vesa
AU - Kosma, Veli-Matti
AU - Mannermaa, Arto
AU - Anton-Culver, Hoda
AU - Shen, Chen-Yang
AU - Brauch, Hiltrud
AU - Peto, Julian
AU - Guénel, Pascal
AU - Kraft, Peter
AU - Couch, Fergus J
AU - Easton, Douglas F
AU - Hall, Per
AU - Chang-Claude, Jenny
AU - GENICA Network
AU - Harth, Volker
PY - 2013/4/1
Y1 - 2013/4/1
N2 - Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
AB - Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
KW - Breast Neoplasms
KW - Carcinoma, Ductal, Breast
KW - Carcinoma, Lobular
KW - Case-Control Studies
KW - Chromosomes, Human
KW - Estrogen Replacement Therapy
KW - Estrogens
KW - Female
KW - Genetic Loci
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Linkage Disequilibrium
KW - Polymorphism, Single Nucleotide
KW - Postmenopause
KW - Progestins
KW - Risk Factors
KW - Sequence Analysis, DNA
U2 - 10.1007/s10549-013-2443-z
DO - 10.1007/s10549-013-2443-z
M3 - SCORING: Journal article
C2 - 23423446
VL - 138
SP - 529
EP - 542
JO - BREAST CANCER RES TR
JF - BREAST CANCER RES TR
SN - 0167-6806
IS - 2
ER -