TY - JOUR
T1 - Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression
T2 - identification of a modifier of breast cancer risk at locus 11q22.3
AU - KConFab Investigators
AU - HEBON
AU - GEMO Study Collaborators
AU - EMBRACE
AU - Hamdi, Yosr
AU - Soucy, Penny
AU - Kuchenbaeker, Karoline B.
AU - Pastinen, Tomi
AU - Droit, Arnaud
AU - Lemaçon, Audrey
AU - Adlard, Julian
AU - Aittomäki, Kristiina
AU - Andrulis, Irene L.
AU - Arason, Adalgeir
AU - Arnold, Norbert
AU - Arun, Banu K.
AU - Azzollini, Jacopo
AU - Bane, Anita
AU - Barjhoux, Laure
AU - Barrowdale, Daniel
AU - Benitez, Javier
AU - Berthet, Pascaline
AU - Blok, Marinus J.
AU - Bobolis, Kristie
AU - Bonadona, Valérie
AU - Bonanni, Bernardo
AU - Bradbury, Angela R.
AU - Brewer, Carole
AU - Buecher, Bruno
AU - Buys, Saundra S.
AU - Caligo, Maria A.
AU - Chiquette, Jocelyne
AU - Chung, Wendy K.
AU - Claes, Kathleen B.M.
AU - Daly, Mary B.
AU - Damiola, Francesca
AU - Davidson, Rosemarie
AU - De la Hoya, Miguel
AU - De Leeneer, Kim
AU - Diez, Orland
AU - Ding, Yuan Chun
AU - Dolcetti, Riccardo
AU - Domchek, Susan M.
AU - Dorfling, Cecilia M.
AU - Eccles, Diana
AU - Eeles, Ros
AU - Einbeigi, Zakaria
AU - Ejlertsen, Bent
AU - Engel, Christoph
AU - Gareth Evans, D.
AU - Feliubadalo, Lidia
AU - Foretova, Lenka
AU - Fostira, Florentia
AU - Foulkes, William D.
N1 - Publisher Copyright:
© 2016, The Author(s).
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
AB - Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
KW - BRCA1 and BRCA2 mutation carriers
KW - Breast cancer
KW - Cis-regulatory variants
KW - Differential allelic expression
KW - Genetic modifiers
KW - Genetic susceptibility
UR - http://www.scopus.com/inward/record.url?scp=84992735226&partnerID=8YFLogxK
U2 - 10.1007/s10549-016-4018-2
DO - 10.1007/s10549-016-4018-2
M3 - Article
C2 - 27796716
SN - 0167-6806
VL - 161
SP - 117
EP - 134
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 1
ER -
