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

Y. Hamdi, P. Soucy, K.B. Kuchenbaeker, T. Pastinen, A. Droit, A. Lemaçon, J. Adlard, K. Aittomäki, I.L. Andrulis, A. Arason, N. Arnold, B.K. Arun, J. Azzollini, A. Bane, L. Barjhoux, D. Barrowdale, J. Benitez, P. Berthet, M.J. Blok, K. BobolisV. Bonadona, B. Bonanni, A.R. Bradbury, C. Brewer, B. Buecher, S.S. Buys, M.A. Caligo, J. Chiquette, W.K. Chung, K.B.M. Claes, M.B. Daly, F. Damiola, R. Davidson, M. De la Hoya, K. De Leeneer, O. Diez, Y.C. Ding, R. Dolcetti, S.M. Domchek, C.M. Dorfling, D. Eccles, R. Eeles, Z. Einbeigi, B. Ejlertsen, EMBRACE [Unknown], C. Engel, D. Gareth Evans, L. Feliubadalo, L. Foretova, F. Fostira, W.D. Foulkes, G. Fountzilas, E. Friedman, D. Frost, P. Ganschow, P.A. Ganz, J. Garber, S.A. Gayther, GEMO Study Collaborators, A.-M. Gerdes, G. Glendon, A.K. Godwin, D.E. Goldgar, M.H. Greene, J. Gronwald, E. Hahnen, U. Hamann, T.V.O. Hansen, S. Hart, J.L. Hays, HEBON [Unknown], F.B.L. Hogervorst, P.J. Hulick, E.N. Imyanitov, C. Isaacs, L. Izatt, A. Jakubowska, P. James, R. Janavicius, U.B. Jensen, E.M. John, V. Joseph, W. Just, K. Kaczmarek, B.Y. Karlan, KConFab Investigators, C.M. Kets, J. Kirk, M. Kriege, Y. Laitman, M. Laurent, C. Lazaro, G. Leslie, J. Lester, F. Lesueur, A. Liljegren, N. Loman, J.T. Loud, S. Manoukian, M. Mariani, S. Mazoyer, L. McGuffog, H.E.J. Meijers-Heijboer, A. Meindl, A. Miller, M. Montagna, A.M. Mulligan, K.L. Nathanson, S.L. Neuhausen, H. Nevanlinna, R.L. Nussbaum, E. Olah, O.I. Olopade, K.-R. Ong, J.C. Oosterwijk, A. Osorio, L. Papi, S.K. Park, I.S. Pedersen, B. Peissel, P.P. Segura, P. Peterlongo, C.M. Phelan, P. Radice, J. Rantala, C. Rappaport-Fuerhauser, G. Rennert, A. Richardson, M. Robson, G.C. Rodriguez, M.A. Rookus, R.K. Schmutzler, N. Sevenet, P.D. Shah, C.F. Singer, T.P. Slavin, K. Snape, J. Sokolowska, I.M.H. Sønderstrup, M. Southey, A.B. Spurdle, Z. Stadler, D. Stoppa-Lyonnet, G. Sukiennicki, C. Sutter, Y. Tan, M.-K. Tea, M.R. Teixeira, A. Teulé, S.-H. Teo, M.B. Terry, M. Thomassen, L. Tihomirova, M. Tischkowitz, S. Tognazzo, A.E. Toland, N. Tung, A.M.W. van den Ouweland, R.B. van der Luijt, K. van Engelen, E.J. van Rensburg, R. Varon-Mateeva, B. Wappenschmidt, J.T. Wijnen, T. Rebbeck, G. Chenevix-Trench, K. Offit, F.J. Couch, S. Nord, D.F. Easton, A.C. Antoniou, J. Simard

Research output: Contribution to journalArticlepeer-review

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. © 2016, The Author(s).
Original languageEnglish
Pages (from-to)117-134
Number of pages18
JournalBreast Cancer Research and Treatment
Volume161
Issue number1
DOIs
Publication statusPublished - 2017

Keywords

  • BRCA1 and BRCA2 mutation carriers
  • Breast cancer
  • Cis-regulatory variants
  • Differential allelic expression
  • Genetic modifiers
  • Genetic susceptibility
  • ACAT1 gene
  • adult
  • Article
  • ATM gene
  • breast cancer
  • cancer risk
  • cancer susceptibility
  • chromosome 11q
  • computer model
  • controlled study
  • female
  • gene
  • gene expression
  • gene locus
  • gene mutation
  • genetic association
  • genetic variability
  • heterozygote
  • human
  • major clinical study
  • NPAT gene
  • oncogene
  • priority journal
  • quantitative trait locus
  • single nucleotide polymorphism
  • tumor suppressor gene
  • allele
  • breast tumor
  • chromosome 11
  • genetic predisposition
  • genetic variation
  • mutation
  • risk
  • tumor marker
  • Alleles
  • Biomarkers, Tumor
  • Breast Neoplasms
  • Chromosomes, Human, Pair 11
  • Female
  • Gene Expression
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heterozygote
  • Humans
  • Mutation
  • Quantitative Trait Loci
  • Risk

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