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

Rebecca Hein, Dieter Flesch-Janys, Norbert Dahmen, Lars Beckmann, Sara Lindström, Nils Schoof, Kamila Czene, Kirstin Mittelstraß, Thomas Illig, Petra Seibold, Sabine Behrens, Keith Humphreys, Jingmei Li, Jianjun Liu, Janet E Olson, Xianshu Wang, Susan E. Hankinson, Thérèse Truong, Florence Menegaux, Isabel Dos Santos SilvaNichola Johnson, Shou Tung Chen, Jyh Cherng Yu, Argyrios Ziogas, Vesa Kataja, Veli Matti Kosma, Arto Mannermaa, Hoda Anton-Culver, Chen Yang Shen, Hiltrud Brauch, Julian Peto, Pascal Guénel, Peter Kraft, Fergus J Couch, Douglas F. Easton, Per Hall, Jenny Chang-Claude

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)529-542
Number of pages14
JournalBreast Cancer Research and Treatment
Volume138
Issue number2
DOIs
StatePublished - Apr 2013

Fingerprint

Genetic Loci
Genome-Wide Association Study
Genetic Predisposition to Disease
Hormones
Breast Neoplasms
Single Nucleotide Polymorphism
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 18
Therapeutics
Case-Control Studies
Joints
Chromosomes, Human, Pair 7
Linkage Disequilibrium
Carcinogenesis
Genome

Keywords

  • Case-only study
  • Gene-environment interaction
  • Genome-wide association study
  • Menopausal hormone therapy
  • Polymorphisms
  • Postmenopausal breast cancer risk

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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.

In: Breast Cancer Research and Treatment, Vol. 138, No. 2, 04.2013, p. 529-542.

Research output: Contribution to journalArticle

Hein, R, Flesch-Janys, D, Dahmen, N, Beckmann, L, Lindström, S, Schoof, N, Czene, K, Mittelstraß, K, Illig, T, Seibold, P, Behrens, S, Humphreys, K, Li, J, Liu, J, Olson, JE, Wang, X, Hankinson, SE, Truong, T, Menegaux, F, Dos Santos Silva, I, Johnson, N, Chen, ST, Yu, JC, Ziogas, A, Kataja, V, Kosma, VM, Mannermaa, A, Anton-Culver, H, Shen, CY, Brauch, H, Peto, J, Guénel, P, Kraft, P, Couch, FJ, Easton, DF, Hall, P & Chang-Claude, J 2013, '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', Breast Cancer Research and Treatment, vol. 138, no. 2, pp. 529-542. https://doi.org/10.1007/s10549-013-2443-z
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. / 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. In: Breast Cancer Research and Treatment. 2013 ; Vol. 138, No. 2. pp. 529-542.
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abstract = "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.",
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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

T2 - 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

PY - 2013/4

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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.

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KW - Case-only study

KW - Gene-environment interaction

KW - Genome-wide association study

KW - Menopausal hormone therapy

KW - Polymorphisms

KW - Postmenopausal breast cancer risk

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