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; 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; P. M. Webb; A. Green; P. Parsons; N. Hayward; 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

doi:10.1530/ERC-13-0349

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 LissowskaJonine 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, P. M. Webb, A. Green, P. Parsons, N. Hayward, 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 journal › Article › peer-review

18 Scopus citations

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 language	English (US)
Pages (from-to)	875-887
Number of pages	13
Journal	Endocrine-related cancer
Volume	20
Issue number	6
DOIs	https://doi.org/10.1530/ERC-13-0349
State	Published - Dec 1 2013
Externally published	Yes

Keywords

Breast cancer
Genetic variation
Genome-wide
Menopausal hormone therapy

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Oncology
Endocrinology
Cancer Research

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10.1530/ERC-13-0349

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Rudolph, A., Hein, R., Lindström, S., Beckmann, L., Behrens, S., Liu, J., Aschard, H., Bolla, M. K., Wang, J., Truong, T., Cordina-Duverger, E., Menegaux, F., Brüning, T., Harth, V., Lo, W. Y., Severi, G., Baglietto, L., Southey, M., Chanock, S. 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

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, 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

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title = "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!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.",

keywords = "Breast cancer, Genetic variation, Genome-wide, Menopausal hormone therapy",

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

year = "2013",

month = dec,

day = "1",

doi = "10.1530/ERC-13-0349",

language = "English (US)",

volume = "20",

pages = "875--887",

journal = "Endocrine-related cancer",

issn = "1351-0088",

publisher = "Society for Endocrinology",

number = "6",

}

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, P. M.

AU - Green, A.

AU - Parsons, P.

AU - Hayward, N.

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 - 2013/12/1

Y1 - 2013/12/1

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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JO - Endocrine-related cancer

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

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