1. 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.
- Author
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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 KB, 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, 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, Gerdes AM, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gronwald J, Hahnen E, Hamann U, Hansen TV, Hart S, Hays JL, Hogervorst FB, 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, 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 HE, Meindl A, Miller A, Montagna M, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Nussbaum RL, Olah E, Olopade OI, Ong KR, 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 IM, Southey M, Spurdle AB, Stadler Z, Stoppa-Lyonnet D, Sukiennicki G, Sutter C, Tan Y, Tea MK, Teixeira MR, Teulé A, Teo SH, Terry MB, Thomassen M, Tihomirova L, Tischkowitz M, Tognazzo S, Toland AE, Tung N, van den Ouweland AM, 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, and Simard J
- Subjects
- Biomarkers, Tumor, Chromosomes, Human, Pair 11, Female, Gene Expression, Genetic Predisposition to Disease, Genetic Variation, Humans, Quantitative Trait Loci, Risk, Alleles, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Genes, BRCA1, Genes, BRCA2, Heterozygote, Mutation
- 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., Competing Interests: The authors declare that they have no conflict of interest. Ethical approval Study participants were recruited through the CIMBA Initiative, following the approval of the corresponding protocol by the Institutional Review Board or Ethics Committee at each participating center. Written informed consent was obtained from all study participants.- Published
- 2017
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