Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk

A genome-wide interaction study

Anja Rudolph, Rebecca Hein, Sara Lindström, Lars Beckmann, Sabine Behrens, Jianjun Liu, Hugues Aschard, Manjeet K. Bolla, Jean Wang, Therese Truong, Emilie Cordina-Duverger, Florence Menegaux, Thomas Brüning, Volker Harth, Wing Yee Lo, Gianluca Severi, Laura Baglietto, Melissa Southey, Stephen J. Chanock, Jolanta Lissowska & 35 others Jonine D. Figueroa, Mikael Eriksson, Keith Humpreys, Hatef Darabi, Janet E. Olson, Kristen N. Stevens, Celine M. Vachon, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Penny M. Webb, A. Green, P. Parsons, N. Hayward, P. M. Webb, D. Whiteman, Pascal Guenel, Hiltrud Brauch, Graham Giles, Montserrat Garca-Closas, Kamila Czene, Georgia Chenevix-Trench, Fergus J. Couch, Irene L. Andrulis, Anthony Swerdlow, David J. Hunter, Dieter Flesch-Janys, Douglas F. Easton, Per Hall, Heli Nevanlinna, Peter Kraft, Jenny Chang-Claude

Research output: Contribution to journalArticle

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!10K3 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!10K6), two SNPs in SLC25A21 (combined Pint%4.8!10K5), and three SNPs in PLCG2 (combined Pint%4.5!10K5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint%2.7!10K5), one SNP in CD80 (combined Pint%8.2!10K6), three SNPs on chr17 near TMEM132E (combined Pint%2.2! 10K6), and two SNPs on chr18 near SLC25A52 (combined Pint%4.6!10K5). 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.

Original languageEnglish (US)
Pages (from-to)875-887
Number of pages13
JournalEndocrine-Related Cancer
Volume20
Issue number6
DOIs
StatePublished - Dec 2013
Externally publishedYes

Fingerprint

Hormone Replacement Therapy
Single Nucleotide Polymorphism
Genome
Breast Neoplasms
Hormones
Meta-Analysis
Therapeutics
Genome-Wide Association Study
Case-Control Studies
Mitochondria

Keywords

  • Breast cancer
  • Genetic variation
  • Genome-wide
  • Menopausal hormone therapy

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

Rudolph, A., Hein, R., Lindström, S., Beckmann, L., Behrens, S., Liu, J., ... Chang-Claude, J. (2013). Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: A genome-wide interaction study. Endocrine-Related Cancer, 20(6), 875-887. https://doi.org/10.1530/ERC-13-0349

Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk : A genome-wide interaction study. / Rudolph, Anja; Hein, Rebecca; Lindström, Sara; Beckmann, Lars; Behrens, Sabine; Liu, Jianjun; Aschard, Hugues; Bolla, Manjeet K.; Wang, Jean; Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence; Brüning, Thomas; Harth, Volker; Lo, Wing Yee; Severi, Gianluca; Baglietto, Laura; Southey, Melissa; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Eriksson, Mikael; Humpreys, Keith; Darabi, Hatef; Olson, Janet E.; Stevens, Kristen N.; Vachon, Celine M.; Knight, Julia A.; Glendon, Gord; Marie Mulligan, Anna; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk; Webb, Penny M.; Green, A.; Parsons, P.; Hayward, N.; Webb, P. M.; Whiteman, D.; Guenel, Pascal; Brauch, Hiltrud; Giles, Graham; Garca-Closas, Montserrat; Czene, Kamila; Chenevix-Trench, Georgia; Couch, Fergus J.; Andrulis, Irene L.; Swerdlow, Anthony; Hunter, David J.; Flesch-Janys, Dieter; Easton, Douglas F.; Hall, Per; Nevanlinna, Heli; Kraft, Peter; Chang-Claude, Jenny.

In: Endocrine-Related Cancer, Vol. 20, No. 6, 12.2013, p. 875-887.

Research output: Contribution to journalArticle

Rudolph, A, Hein, R, Lindström, S, Beckmann, L, Behrens, S, Liu, J, Aschard, H, Bolla, MK, Wang, J, Truong, T, Cordina-Duverger, E, Menegaux, F, Brüning, T, Harth, V, Lo, WY, 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, Marie Mulligan, A, Ashworth, A, Orr, N, Schoemaker, M, Webb, PM, Green, A, Parsons, P, Hayward, N, Webb, PM, Whiteman, D, Guenel, P, Brauch, H, Giles, G, Garca-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 2013, 'Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: A genome-wide interaction study', Endocrine-Related Cancer, vol. 20, no. 6, pp. 875-887. https://doi.org/10.1530/ERC-13-0349
Rudolph, Anja ; Hein, Rebecca ; Lindström, Sara ; Beckmann, Lars ; Behrens, Sabine ; Liu, Jianjun ; Aschard, Hugues ; Bolla, Manjeet K. ; Wang, Jean ; Truong, Therese ; Cordina-Duverger, Emilie ; Menegaux, Florence ; Brüning, Thomas ; Harth, Volker ; Lo, Wing Yee ; Severi, Gianluca ; Baglietto, Laura ; Southey, Melissa ; Chanock, Stephen J. ; Lissowska, Jolanta ; Figueroa, Jonine D. ; Eriksson, Mikael ; Humpreys, Keith ; Darabi, Hatef ; Olson, Janet E. ; Stevens, Kristen N. ; Vachon, Celine M. ; Knight, Julia A. ; Glendon, Gord ; Marie Mulligan, Anna ; Ashworth, Alan ; Orr, Nicholas ; Schoemaker, Minouk ; Webb, Penny M. ; Green, A. ; Parsons, P. ; Hayward, N. ; Webb, P. M. ; Whiteman, D. ; Guenel, Pascal ; Brauch, Hiltrud ; Giles, Graham ; Garca-Closas, Montserrat ; Czene, Kamila ; Chenevix-Trench, Georgia ; Couch, Fergus J. ; Andrulis, Irene L. ; Swerdlow, Anthony ; Hunter, David J. ; Flesch-Janys, Dieter ; Easton, Douglas F. ; Hall, Per ; Nevanlinna, Heli ; Kraft, Peter ; Chang-Claude, Jenny. / Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk : A genome-wide interaction study. In: Endocrine-Related Cancer. 2013 ; Vol. 20, No. 6. pp. 875-887.
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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!10K3 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!10K6), two SNPs in SLC25A21 (combined Pint{\%}4.8!10K5), and three SNPs in PLCG2 (combined Pint{\%}4.5!10K5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint{\%}2.7!10K5), one SNP in CD80 (combined Pint{\%}8.2!10K6), three SNPs on chr17 near TMEM132E (combined Pint{\%}2.2! 10K6), and two SNPs on chr18 near SLC25A52 (combined Pint{\%}4.6!10K5). 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.",
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TY - JOUR

T1 - Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk

T2 - A genome-wide interaction study

AU - Rudolph, Anja

AU - Hein, Rebecca

AU - Lindström, Sara

AU - Beckmann, Lars

AU - Behrens, Sabine

AU - Liu, Jianjun

AU - Aschard, Hugues

AU - Bolla, Manjeet K.

AU - Wang, Jean

AU - Truong, Therese

AU - Cordina-Duverger, Emilie

AU - Menegaux, Florence

AU - Brüning, Thomas

AU - Harth, Volker

AU - Lo, Wing Yee

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - Southey, Melissa

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Figueroa, Jonine D.

AU - Eriksson, Mikael

AU - Humpreys, Keith

AU - Darabi, Hatef

AU - Olson, Janet E.

AU - Stevens, Kristen N.

AU - Vachon, Celine M.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Marie Mulligan, Anna

AU - Ashworth, Alan

AU - Orr, Nicholas

AU - Schoemaker, Minouk

AU - Webb, Penny M.

AU - Green, A.

AU - Parsons, P.

AU - Hayward, N.

AU - Webb, P. M.

AU - Whiteman, D.

AU - Guenel, Pascal

AU - Brauch, Hiltrud

AU - Giles, Graham

AU - Garca-Closas, Montserrat

AU - Czene, Kamila

AU - Chenevix-Trench, Georgia

AU - Couch, Fergus J.

AU - Andrulis, Irene L.

AU - Swerdlow, Anthony

AU - Hunter, David J.

AU - Flesch-Janys, Dieter

AU - Easton, Douglas F.

AU - Hall, Per

AU - Nevanlinna, Heli

AU - Kraft, Peter

AU - Chang-Claude, Jenny

PY - 2013/12

Y1 - 2013/12

N2 - 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!10K3 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!10K6), two SNPs in SLC25A21 (combined Pint%4.8!10K5), and three SNPs in PLCG2 (combined Pint%4.5!10K5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint%2.7!10K5), one SNP in CD80 (combined Pint%8.2!10K6), three SNPs on chr17 near TMEM132E (combined Pint%2.2! 10K6), and two SNPs on chr18 near SLC25A52 (combined Pint%4.6!10K5). 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.

AB - 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!10K3 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!10K6), two SNPs in SLC25A21 (combined Pint%4.8!10K5), and three SNPs in PLCG2 (combined Pint%4.5!10K5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint%2.7!10K5), one SNP in CD80 (combined Pint%8.2!10K6), three SNPs on chr17 near TMEM132E (combined Pint%2.2! 10K6), and two SNPs on chr18 near SLC25A52 (combined Pint%4.6!10K5). 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.

KW - Breast cancer

KW - Genetic variation

KW - Genome-wide

KW - Menopausal hormone therapy

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