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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.

Hamdi, Y; Soucy, P; Kuchenbaeker, KB; Pastinen, T; Droit, A; Lemaçon, A; Adlard, J; Aittomäki, K; Andrulis, IL; Arason, A; et al. 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 (2017) 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. Breast Cancer Res Treat, 161 (1). pp. 117-134. ISSN 1573-7217 https://doi.org/10.1007/s10549-016-4018-2
SGUL Authors: Snape, Katie Mairwen Greenwood

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Abstract

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.

Item Type: Article
Additional Information: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: BRCA1 and BRCA2 mutation carriers, Breast cancer, Cis-regulatory variants, Differential allelic expression, Genetic modifiers, Genetic susceptibility, Oncology & Carcinogenesis, 1112 Oncology And Carcinogenesis
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Breast Cancer Res Treat
ISSN: 1573-7217
Language: eng
Dates:
DateEvent
1 January 2017Published
28 October 2016Published Online
8 October 2016Accepted
Projects:
Project IDFunderFunder ID
U10 CA180868NCI NIH HHSUNSPECIFIED
R01 CA140323NCI NIH HHSUNSPECIFIED
R01 CA176785NCI NIH HHSUNSPECIFIED
RC4 CA153828NCI NIH HHSUNSPECIFIED
R01 CA142996NCI NIH HHSUNSPECIFIED
P50 CA125183NCI NIH HHSUNSPECIFIED
UM1 CA164920NCI NIH HHSUNSPECIFIED
P30 CA168524NCI NIH HHSUNSPECIFIED
U01 CA161032NCI NIH HHSUNSPECIFIED
U10 CA027469NCI NIH HHSUNSPECIFIED
UL1 TR000124NCATS NIH HHSUNSPECIFIED
U01 CA116167NCI NIH HHSUNSPECIFIED
R01 CA128978NCI NIH HHSUNSPECIFIED
R01 CA083855NCI NIH HHSUNSPECIFIED
U19 CA148537NCI NIH HHSUNSPECIFIED
P30 CA051008NCI NIH HHSUNSPECIFIED
R01 CA116167NCI NIH HHSUNSPECIFIED
P50 CA116201NCI NIH HHSUNSPECIFIED
U01 CA113916NCI NIH HHSUNSPECIFIED
U10 CA037517NCI NIH HHSUNSPECIFIED
N02CP65504NCI NIH HHSUNSPECIFIED
R01 CA102776NCI NIH HHSUNSPECIFIED
U19 CA148112NCI NIH HHSUNSPECIFIED
R01 CA149429NCI NIH HHSUNSPECIFIED
U19 CA148065NCI NIH HHSUNSPECIFIED
R01 CA192393NCI NIH HHSUNSPECIFIED
U10 CA180822NCI NIH HHSUNSPECIFIED
N02CP11019NCI NIH HHSUNSPECIFIED
PubMed ID: 27796716
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/108605
Publisher's version: https://doi.org/10.1007/s10549-016-4018-2

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