Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.
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.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Foundation for Quality and Efficiency in Health Care (IQWIG), Cologne, Germany Human Genetics, Genome Institute of Singapore, Singapore, Singapore Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK INSERM (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France Unité Mixte de Recherche Scientifique (UMRS) 1018, University Paris-Sud, Villejuif, France Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bochum, Germany Institute for Occupational Medicine and Maritime Medicine, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany Institute of Pathology, University of Bonn, Bonn, Germany Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia Division of Cancer Epidemiology and Genetics, N
Anja
A
Rudolph
Rebecca
R
Hein
Sara
S
Lindström
Lars
L
Beckmann
Sabine
S
Behrens
Jianjun
J
Liu
Hugues
H
Aschard
Manjeet K
MK
Bolla
Jean
J
Wang
Thérèse
T
Truong
Emilie
E
Cordina-Duverger
Florence
F
Menegaux
Thomas
T
Brüning
Volker
V
Harth
Gianluca
G
Severi
Laura
L
Baglietto
Melissa
M
Southey
Stephen J
SJ
Chanock
Jolanta
J
Lissowska
Jonine D
JD
Figueroa
Mikael
M
Eriksson
Keith
K
Humpreys
Hatef
H
Darabi
Janet E
JE
Olson
Kristen N
KN
Stevens
Celine M
CM
Vachon
Julia A
JA
Knight
Gord
G
Glendon
Anna Marie
AM
Mulligan
Alan
A
Ashworth
Nicholas
N
Orr
Minouk
M
Schoemaker
Penny M
PM
Webb
Pascal
P
Guénel
Hiltrud
H
Brauch
Graham
G
Giles
Montserrat
M
García-Closas
Kamila
K
Czene
Georgia
G
Chenevix-Trench
Fergus J
FJ
Couch
Irene L
IL
Andrulis
Anthony
A
Swerdlow
David J
DJ
Hunter
Dieter
D
Flesch-Janys
Douglas F
DF
Easton
Per
P
Hall
Heli
H
Nevanlinna
Peter
P
Kraft
Jenny
J
Chang-Claude
D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000209:etiology*; D018275:Carcinoma, Lobular / Q000209:etiology*; D016022:Case-Control Studies; D005260:Female; D060045:Genes, Modifier / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors
D014408:Biomarkers, Tumor
breast cancer; genetic variation; genome-wide; menopausal hormone therapy