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Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.


ABSTRACT: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

SUBMITTER: Vigorito E 

PROVIDER: S-EPMC4963094 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Vigorito Elena E   Kuchenbaecker Karoline B KB   Beesley Jonathan J   Adlard Julian J   Agnarsson Bjarni A BA   Andrulis Irene L IL   Arun Banu K BK   Barjhoux Laure L   Belotti Muriel M   Benitez Javier J   Berger Andreas A   Bojesen Anders A   Bonanni Bernardo B   Brewer Carole C   Caldes Trinidad T   Caligo Maria A MA   Campbell Ian I   Chan Salina B SB   Claes Kathleen B M KB   Cohn David E DE   Cook Jackie J   Daly Mary B MB   Damiola Francesca F   Davidson Rosemarie R   Pauw Antoine de Ad   Delnatte Capucine C   Diez Orland O   Domchek Susan M SM   Dumont Martine M   Durda Katarzyna K   Dworniczak Bernd B   Easton Douglas F DF   Eccles Diana D   Edwinsdotter Ardnor Christina C   Eeles Ros R   Ejlertsen Bent B   Ellis Steve S   Evans D Gareth DG   Feliubadalo Lidia L   Fostira Florentia F   Foulkes William D WD   Friedman Eitan E   Frost Debra D   Gaddam Pragna P   Ganz Patricia A PA   Garber Judy J   Garcia-Barberan Vanesa V   Gauthier-Villars Marion M   Gehrig Andrea A   Gerdes Anne-Marie AM   Giraud Sophie S   Godwin Andrew K AK   Goldgar David E DE   Hake Christopher R CR   Hansen Thomas V O TV   Healey Sue S   Hodgson Shirley S   Hogervorst Frans B L FB   Houdayer Claude C   Hulick Peter J PJ   Imyanitov Evgeny N EN   Isaacs Claudine C   Izatt Louise L   Izquierdo Angel A   Jacobs Lauren L   Jakubowska Anna A   Janavicius Ramunas R   Jaworska-Bieniek Katarzyna K   Jensen Uffe Birk UB   John Esther M EM   Vijai Joseph J   Karlan Beth Y BY   Kast Karin K   Khan Sofia S   Kwong Ava A   Laitman Yael Y   Lester Jenny J   Lesueur Fabienne F   Liljegren Annelie A   Lubinski Jan J   Mai Phuong L PL   Manoukian Siranoush S   Mazoyer Sylvie S   Meindl Alfons A   Mensenkamp Arjen R AR   Montagna Marco M   Nathanson Katherine L KL   Neuhausen Susan L SL   Nevanlinna Heli H   Niederacher Dieter D   Olah Edith E   Olopade Olufunmilayo I OI   Ong Kai-Ren KR   Osorio Ana A   Park Sue Kyung SK   Paulsson-Karlsson Ylva Y   Pedersen Inge Sokilde IS   Peissel Bernard B   Peterlongo Paolo P   Pfeiler Georg G   Phelan Catherine M CM   Piedmonte Marion M   Poppe Bruce B   Pujana Miquel Angel MA   Radice Paolo P   Rennert Gad G   Rodriguez Gustavo C GC   Rookus Matti A MA   Ross Eric A EA   Schmutzler Rita Katharina RK   Simard Jacques J   Singer Christian F CF   Slavin Thomas P TP   Soucy Penny P   Southey Melissa M   Steinemann Doris D   Stoppa-Lyonnet Dominique D   Sukiennicki Grzegorz G   Sutter Christian C   Szabo Csilla I CI   Tea Muy-Kheng MK   Teixeira Manuel R MR   Teo Soo-Hwang SH   Terry Mary Beth MB   Thomassen Mads M   Tibiletti Maria Grazia MG   Tihomirova Laima L   Tognazzo Silvia S   van Rensburg Elizabeth J EJ   Varesco Liliana L   Varon-Mateeva Raymonda R   Vratimos Athanassios A   Weitzel Jeffrey N JN   McGuffog Lesley L   Kirk Judy J   Toland Amanda Ewart AE   Hamann Ute U   Lindor Noralane N   Ramus Susan J SJ   Greene Mark H MH   Couch Fergus J FJ   Offit Kenneth K   Pharoah Paul D P PD   Chenevix-Trench Georgia G   Antoniou Antonis C AC  

PloS one 20160727 7


Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer a  ...[more]

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