Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.
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Date
2017-01-01ICR Author
Author
Hamdi, Y
Soucy, P
Kuchenbaeker, KB
Pastinen, T
Droit, A
Lemaçon, A
Adlard, J
Aittomäki, K
Andrulis, IL
Arason, A
Arnold, N
Arun, BK
Azzollini, J
Bane, A
Barjhoux, L
Barrowdale, D
Benitez, J
Berthet, P
Blok, MJ
Bobolis, K
Bonadona, V
Bonanni, B
Bradbury, AR
Brewer, C
Buecher, B
Buys, SS
Caligo, MA
Chiquette, J
Chung, WK
Claes, KBM
Daly, MB
Damiola, F
Davidson, R
De la Hoya, M
De Leeneer, K
Diez, O
Ding, YC
Dolcetti, R
Domchek, SM
Dorfling, CM
Eccles, D
Eeles, R
Einbeigi, Z
Ejlertsen, B
EMBRACE,
Engel, C
Gareth Evans, D
Feliubadalo, L
Foretova, L
Fostira, F
Foulkes, WD
Fountzilas, G
Friedman, E
Frost, D
Ganschow, P
Ganz, PA
Garber, J
Gayther, SA
GEMO Study Collaborators,
Gerdes, A-M
Glendon, G
Godwin, AK
Goldgar, DE
Greene, MH
Gronwald, J
Hahnen, E
Hamann, U
Hansen, TVO
Hart, S
Hays, JL
HEBON,
Hogervorst, FBL
Hulick, PJ
Imyanitov, EN
Isaacs, C
Izatt, L
Jakubowska, A
James, P
Janavicius, R
Jensen, UB
John, EM
Joseph, V
Just, W
Kaczmarek, K
Karlan, BY
KConFab Investigators,
Kets, CM
Kirk, J
Kriege, M
Laitman, Y
Laurent, M
Lazaro, C
Leslie, G
Lester, J
Lesueur, F
Liljegren, A
Loman, N
Loud, JT
Manoukian, S
Mariani, M
Mazoyer, S
McGuffog, L
Meijers-Heijboer, HEJ
Meindl, A
Miller, A
Montagna, M
Mulligan, AM
Nathanson, KL
Neuhausen, SL
Nevanlinna, H
Nussbaum, RL
Olah, E
Olopade, OI
Ong, K-R
Oosterwijk, JC
Osorio, A
Papi, L
Park, SK
Pedersen, IS
Peissel, B
Segura, PP
Peterlongo, P
Phelan, CM
Radice, P
Rantala, J
Rappaport-Fuerhauser, C
Rennert, G
Richardson, A
Robson, M
Rodriguez, GC
Rookus, MA
Schmutzler, RK
Sevenet, N
Shah, PD
Singer, CF
Slavin, TP
Snape, K
Sokolowska, J
Sønderstrup, IMH
Southey, M
Spurdle, AB
Stadler, Z
Stoppa-Lyonnet, D
Sukiennicki, G
Sutter, C
Tan, Y
Tea, M-K
Teixeira, MR
Teulé, A
Teo, S-H
Terry, MB
Thomassen, M
Tihomirova, L
Tischkowitz, M
Tognazzo, S
Toland, AE
Tung, N
van den Ouweland, AMW
van der Luijt, RB
van Engelen, K
van Rensburg, EJ
Varon-Mateeva, R
Wappenschmidt, B
Wijnen, JT
Rebbeck, T
Chenevix-Trench, G
Offit, K
Couch, FJ
Nord, S
Easton, DF
Antoniou, AC
Simard, J
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
EMBRACE
GEMO Study Collaborators
HEBON
KConFab Investigators
Chromosomes, Human, Pair 11
Humans
Breast Neoplasms
Genetic Predisposition to Disease
Risk
Gene Expression
Heterozygote
Mutation
Alleles
Genes, BRCA1
Genes, BRCA2
Quantitative Trait Loci
Female
Genetic Variation
Biomarkers, Tumor
Research team
Oncogenetics
Language
eng
Date accepted
2016-10-08
License start date
2017-01
Citation
Breast cancer research and treatment, 2017, 161 (1), pp. 117 - 134
Publisher
SPRINGER