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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.

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.

SUBMITTER: Hamdi Y 

PROVIDER: S-EPMC5222911 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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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 Yosr Y   Soucy Penny P   Kuchenbaeker Karoline B KB   Pastinen Tomi T   Droit Arnaud A   Lemaçon Audrey A   Adlard Julian J   Aittomäki Kristiina K   Andrulis Irene L IL   Arason Adalgeir A   Arnold Norbert N   Arun Banu K BK   Azzollini Jacopo J   Bane Anita A   Barjhoux Laure L   Barrowdale Daniel D   Benitez Javier J   Berthet Pascaline P   Blok Marinus J MJ   Bobolis Kristie K   Bonadona Valérie V   Bonanni Bernardo B   Bradbury Angela R AR   Brewer Carole C   Buecher Bruno B   Buys Saundra S SS   Caligo Maria A MA   Chiquette Jocelyne J   Chung Wendy K WK   Claes Kathleen B M KB   Daly Mary B MB   Damiola Francesca F   Davidson Rosemarie R   De la Hoya Miguel M   De Leeneer Kim K   Diez Orland O   Ding Yuan Chun YC   Dolcetti Riccardo R   Domchek Susan M SM   Dorfling Cecilia M CM   Eccles Diana D   Eeles Ros R   Einbeigi Zakaria Z   Ejlertsen Bent B   Engel Christoph C   Gareth Evans D D   Feliubadalo Lidia L   Foretova Lenka L   Fostira Florentia F   Foulkes William D WD   Fountzilas George G   Friedman Eitan E   Frost Debra D   Ganschow Pamela P   Ganz Patricia A PA   Garber Judy J   Gayther Simon A SA   Gerdes Anne-Marie AM   Glendon Gord G   Godwin Andrew K AK   Goldgar David E DE   Greene Mark H MH   Gronwald Jacek J   Hahnen Eric E   Hamann Ute U   Hansen Thomas V O TV   Hart Steven S   Hays John L JL   Hogervorst Frans B L FB   Hulick Peter J PJ   Imyanitov Evgeny N EN   Isaacs Claudine C   Izatt Louise L   Jakubowska Anna A   James Paul P   Janavicius Ramunas R   Jensen Uffe Birk UB   John Esther M EM   Joseph Vijai V   Just Walter W   Kaczmarek Katarzyna K   Karlan Beth Y BY   Kets Carolien M CM   Kirk Judy J   Kriege Mieke M   Laitman Yael Y   Laurent Maïté M   Lazaro Conxi C   Leslie Goska G   Lester Jenny J   Lesueur Fabienne F   Liljegren Annelie A   Loman Niklas N   Loud Jennifer T JT   Manoukian Siranoush S   Mariani Milena M   Mazoyer Sylvie S   McGuffog Lesley L   Meijers-Heijboer Hanne E J HE   Meindl Alfons A   Miller Austin A   Montagna Marco M   Mulligan Anna Marie AM   Nathanson Katherine L KL   Neuhausen Susan L SL   Nevanlinna Heli H   Nussbaum Robert L RL   Olah Edith E   Olopade Olufunmilayo I OI   Ong Kai-Ren KR   Oosterwijk Jan C JC   Osorio Ana A   Papi Laura L   Park Sue Kyung SK   Pedersen Inge Sokilde IS   Peissel Bernard B   Segura Pedro Perez PP   Peterlongo Paolo P   Phelan Catherine M CM   Radice Paolo P   Rantala Johanna J   Rappaport-Fuerhauser Christine C   Rennert Gad G   Richardson Andrea A   Robson Mark M   Rodriguez Gustavo C GC   Rookus Matti A MA   Schmutzler Rita Katharina RK   Sevenet Nicolas N   Shah Payal D PD   Singer Christian F CF   Slavin Thomas P TP   Snape Katie K   Sokolowska Johanna J   Sønderstrup Ida Marie Heeholm IM   Southey Melissa M   Spurdle Amanda B AB   Stadler Zsofia Z   Stoppa-Lyonnet Dominique D   Sukiennicki Grzegorz G   Sutter Christian C   Tan Yen Y   Tea Muy-Kheng MK   Teixeira Manuel R MR   Teulé Alex A   Teo Soo-Hwang SH   Terry Mary Beth MB   Thomassen Mads M   Tihomirova Laima L   Tischkowitz Marc M   Tognazzo Silvia S   Toland Amanda Ewart AE   Tung Nadine N   van den Ouweland Ans M W AM   van der Luijt Rob B RB   van Engelen Klaartje K   van Rensburg Elizabeth J EJ   Varon-Mateeva Raymonda R   Wappenschmidt Barbara B   Wijnen Juul T JT   Rebbeck Timothy T   Chenevix-Trench Georgia G   Offit Kenneth K   Couch Fergus J FJ   Nord Silje S   Easton Douglas F DF   Antoniou Antonis C AC   Simard Jacques J  

Breast cancer research and treatment 20161028 1

<h4>Purpose</h4>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.<h4>Methods</h4>Using data from a genome-wide map of SNPs associated with a  ...[more]

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