Advanced

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, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B.; Pastinen, Tomi; Droit, Arnaud; Lemaçon, Audrey; Adlard, Julian; Aittomäki, Kristiina; Andrulis, Irene L. and Arason, Adalgeir, et al. (2017) In Breast Cancer Research and Treatment 161(1). p.117-134
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BRCA1 and BRCA2 mutation carriers, Breast cancer, Cis-regulatory variants, Differential allelic expression, Genetic modifiers, Genetic susceptibility
in
Breast Cancer Research and Treatment
volume
161
issue
1
pages
117 - 134
publisher
Springer
external identifiers
  • scopus:84992735226
  • wos:000392188500012
ISSN
0167-6806
DOI
10.1007/s10549-016-4018-2
language
English
LU publication?
yes
id
de205e2a-c0eb-4400-a4ac-d4c9a2c26b2d
date added to LUP
2016-11-16 08:43:50
date last changed
2018-04-29 04:33:07
@article{de205e2a-c0eb-4400-a4ac-d4c9a2c26b2d,
  abstract     = {<p>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<sup>−6</sup>). 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.</p>},
  author       = {Hamdi, Yosr and Soucy, Penny and Kuchenbaeker, Karoline B. and Pastinen, Tomi and Droit, Arnaud and Lemaçon, Audrey and Adlard, Julian and Aittomäki, Kristiina and Andrulis, Irene L. and Arason, Adalgeir and Arnold, Norbert and Arun, Banu K. and Azzollini, Jacopo and Bane, Anita and Barjhoux, Laure and Barrowdale, Daniel and Benitez, Javier and Berthet, Pascaline and Blok, Marinus J. and Bobolis, Kristie and Bonadona, Valérie and Bonanni, Bernardo and Bradbury, Angela R. and Brewer, Carole and Buecher, Bruno and Buys, Saundra S. and Caligo, Maria A. and Chiquette, Jocelyne and Chung, Wendy K. and Claes, Kathleen B M and Daly, Mary B. and Damiola, Francesca and Davidson, Rosemarie and de la Hoya, Miguel and de Leeneer, Kim and Diez, Orland and Ding, Yuan Chun and Dolcetti, Riccardo and Domchek, Susan M. and Dorfling, Cecilia M. and Eccles, Diana and Eeles, Ros and Einbeigi, Zakaria and Ejlertsen, Bent and EMBRACE,  and Engel, Christoph and Gareth Evans, D. and Feliubadalo, Lidia and Foretova, Lenka and Fostira, Florentia and Foulkes, William D. and Fountzilas, George and Friedman, Eitan and Frost, Debra and Ganschow, Pamela and Ganz, Patricia A. and Garber, Judy and Gayther, Simon A. and Gemo Study Collaborators, Study Collaborators and Gerdes, Anne Marie and Glendon, Gord and Godwin, Andrew K. and Goldgar, David E. and Greene, Mark H. and Gronwald, Jacek and Hahnen, Eric and Hamann, Ute and Hansen, Thomas V O and Hart, Steven and Hays, John L. and HEBON,  and Hogervorst, Frans B L and Hulick, Peter J. and Imyanitov, Evgeny N. and Isaacs, Claudine and Izatt, Louise and Jakubowska, Anna and James, Paul and Janavicius, Ramunas and Jensen, Uffe Birk and John, Esther M. and Joseph, Vijai and Just, Walter and Kaczmarek, Katarzyna and Karlan, Beth Y. and Kconfab Investigators, Investigators and Kets, Carolien M. and Kirk, Judy and Kriege, Mieke and Laitman, Yael and Laurent, Maïté and Lazaro, Conxi and Leslie, Goska and Lester, Jenny and Lesueur, Fabienne and Liljegren, Annelie and Loman, Niklas and Loud, Jennifer T. and Manoukian, Siranoush and Mariani, Milena and Mazoyer, Sylvie and McGuffog, Lesley and Meijers-Heijboer, Hanne E J and Meindl, Alfons and Miller, Austin and Montagna, Marco and Mulligan, Anna Marie and Nathanson, Katherine L. and Neuhausen, Susan L. and Nevanlinna, Heli and Nussbaum, Robert L. and Olah, Edith and Olopade, Olufunmilayo I. and Ong, Kai ren and Oosterwijk, Jan C. and Osorio, Ana and Papi, Laura and Park, Sue Kyung and Pedersen, Inge Sokilde and Peissel, Bernard and Segura, Pedro Perez and Peterlongo, Paolo and Phelan, Catherine M. and Radice, Paolo and Rantala, Johanna and Rappaport-Fuerhauser, Christine and Rennert, Gad and Richardson, Andrea and Robson, Mark and Rodriguez, Gustavo C. and Rookus, Matti A. and Schmutzler, Rita Katharina and Sevenet, Nicolas and Shah, Payal D. and Singer, Christian F. and Slavin, Thomas P. and Snape, Katie and Sokolowska, Johanna and Sønderstrup, Ida Marie Heeholm and Southey, Melissa and Spurdle, Amanda B. and Stadler, Zsofia and Stoppa-Lyonnet, Dominique and Sukiennicki, Grzegorz and Sutter, Christian and Tan, Yen and Tea, Muy Kheng and Teixeira, Manuel R. and Teulé, Alex and Teo, Soo Hwang and Terry, Mary Beth and Thomassen, Mads and Tihomirova, Laima and Tischkowitz, Marc and Tognazzo, Silvia and Toland, Amanda Ewart and Tung, Nadine and van Den Ouweland, Ans M W and van der Luijt, Rob B. and van Engelen, Klaartje and van Rensburg, Elizabeth J. and Varon-Mateeva, Raymonda and Wappenschmidt, Barbara and Wijnen, Juul T. and Rebbeck, Timothy and Chenevix-Trench, Georgia and Offit, Kenneth and Couch, Fergus J. and Nord, Silje and Easton, Douglas F. and Antoniou, Antonis C. and Simard, Jacques},
  issn         = {0167-6806},
  keyword      = {BRCA1 and BRCA2 mutation carriers,Breast cancer,Cis-regulatory variants,Differential allelic expression,Genetic modifiers,Genetic susceptibility},
  language     = {eng},
  number       = {1},
  pages        = {117--134},
  publisher    = {Springer},
  series       = {Breast Cancer Research and Treatment},
  title        = {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},
  url          = {http://dx.doi.org/10.1007/s10549-016-4018-2},
  volume       = {161},
  year         = {2017},
}