Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
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Date
2016-07-27ICR Author
Author
Vigorito, E
Kuchenbaecker, KB
Beesley, J
Adlard, J
Agnarsson, BA
Andrulis, IL
Arun, BK
Barjhoux, L
Belotti, M
Benitez, J
Berger, A
Bojesen, A
Bonanni, B
Brewer, C
Caldes, T
Caligo, MA
Campbell, I
Chan, SB
Claes, KBM
Cohn, DE
Cook, J
Daly, MB
Damiola, F
Davidson, R
Pauw, AD
Delnatte, C
Diez, O
Domchek, SM
Dumont, M
Durda, K
Dworniczak, B
Easton, DF
Eccles, D
Edwinsdotter Ardnor, C
Eeles, R
Ejlertsen, B
Ellis, S
Evans, DG
Feliubadalo, L
Fostira, F
Foulkes, WD
Friedman, E
Frost, D
Gaddam, P
Ganz, PA
Garber, J
Garcia-Barberan, V
Gauthier-Villars, M
Gehrig, A
Gerdes, A-M
Giraud, S
Godwin, AK
Goldgar, DE
Hake, CR
Hansen, TVO
Healey, S
Hodgson, S
Hogervorst, FBL
Houdayer, C
Hulick, PJ
Imyanitov, EN
Isaacs, C
Izatt, L
Izquierdo, A
Jacobs, L
Jakubowska, A
Janavicius, R
Jaworska-Bieniek, K
Jensen, UB
John, EM
Vijai, J
Karlan, BY
Kast, K
KConFab Investigators,
Khan, S
Kwong, A
Laitman, Y
Lester, J
Lesueur, F
Liljegren, A
Lubinski, J
Mai, PL
Manoukian, S
Mazoyer, S
Meindl, A
Mensenkamp, AR
Montagna, M
Nathanson, KL
Neuhausen, SL
Nevanlinna, H
Niederacher, D
Olah, E
Olopade, OI
Ong, K-R
Osorio, A
Park, SK
Paulsson-Karlsson, Y
Pedersen, IS
Peissel, B
Peterlongo, P
Pfeiler, G
Phelan, CM
Piedmonte, M
Poppe, B
Pujana, MA
Radice, P
Rennert, G
Rodriguez, GC
Rookus, MA
Ross, EA
Schmutzler, RK
Simard, J
Singer, CF
Slavin, TP
Soucy, P
Southey, M
Steinemann, D
Stoppa-Lyonnet, D
Sukiennicki, G
Sutter, C
Szabo, CI
Tea, M-K
Teixeira, MR
Teo, S-H
Terry, MB
Thomassen, M
Tibiletti, MG
Tihomirova, L
Tognazzo, S
van Rensburg, EJ
Varesco, L
Varon-Mateeva, R
Vratimos, A
Weitzel, JN
McGuffog, L
Kirk, J
Toland, AE
Hamann, U
Lindor, N
Ramus, SJ
Greene, MH
Couch, FJ
Offit, K
Pharoah, PDP
Chenevix-Trench, G
Antoniou, AC
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
KConFab Investigators
Chromosomes, Human, Pair 9
Humans
Ovarian Neoplasms
Genetic Predisposition to Disease
Chromosome Mapping
Polymorphism, Single Nucleotide
Genes, BRCA1
Genes, BRCA2
Female
Genetic Carrier Screening
Research team
Oncogenetics
Language
eng
Date accepted
2016-06-22
License start date
2016-01
Citation
PloS one, 2016, 11 (7), pp. e0158801 - ?
Publisher
PUBLIC LIBRARY SCIENCE