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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, K. B., Pastinen, T., Droit, A., Lemacon, A., Adlard, J., Aittomaki, K., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Azzollini, J., Bane, A., Barjhoux, L., Barrowdale, D., Benitez, J., Berthet, P., Blok, M. J., Bobolis, K., Bonadona, V., Bonanni, B., Bradbury, A. R., Brewer, C., Buecher, B., Buys, S., Caligo, M. A., Chiquette, J., Chung, W. K., Claes, K. B. M., Daly, M. B., Damiola, F., Davidson, R., de la Hoya, M., De Leeneer, K., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Eccles, D., Eeles, R., Einbeigi, Z., Ejlertsen, B., Engel, C., Evans, D. G., Feliubadalo, L., Foretova, L., Fostira, F., Oosterwijk, J. C., EMBRACE, GEMO Study Collaborators, HEBON & kConFab Investigators, Jan-2017, In : Breast Cancer Research and Treatment. 161, 1, p. 117-134 18 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Yosr Hamdi
  • Penny Soucy
  • Karoline B. Kuchenbaeker
  • Tomi Pastinen
  • Arnaud Droit
  • Audrey Lemacon
  • Julian Adlard
  • Kristiina Aittomaki
  • Irene L. Andrulis
  • Adalgeir Arason
  • Norbert Arnold
  • Banu K. Arun
  • Jacopo Azzollini
  • Anita Bane
  • Laure Barjhoux
  • Daniel Barrowdale
  • Javier Benitez
  • Pascaline Berthet
  • Marinus J. Blok
  • Kristie Bobolis
  • Valerie Bonadona
  • Bernardo Bonanni
  • Angela R. Bradbury
  • Carole Brewer
  • Bruno Buecher
  • Saundra Buys
  • Maria A. Caligo
  • Jocelyne Chiquette
  • Wendy K. Chung
  • Kathleen B. M. Claes
  • Mary B. Daly
  • Francesca Damiola
  • Rosemarie Davidson
  • Miguel de la Hoya
  • Kim De Leeneer
  • Orland Diez
  • Yuan Chun Ding
  • Riccardo Dolcetti
  • Susan M. Domchek
  • Cecilia M. Dorfling
  • Diana Eccles
  • Ros Eeles
  • Zakaria Einbeigi
  • Bent Ejlertsen
  • Christoph Engel
  • D. Gareth Evans
  • Lidia Feliubadalo
  • Lenka Foretova
  • Florentia Fostira
  • Jan C. Oosterwijk
  • EMBRACE
  • GEMO Study Collaborators
  • HEBON
  • kConFab Investigators

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.

Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of similar to 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.

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 x 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.

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.

Original languageEnglish
Pages (from-to)117-134
Number of pages18
JournalBreast Cancer Research and Treatment
Volume161
Issue number1
Publication statusPublished - Jan-2017

    Keywords

  • Breast cancer, Genetic modifiers, Differential allelic expression, Genetic susceptibility, Cis-regulatory variants, BRCA1 and BRCA2 mutation carriers, OVARIAN-CANCER, CYCLIN E-CDK2, HUMAN-CELLS, DISEASE, NPAT, INVESTIGATORS, CONSORTIUM, DNA

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