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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

E Vigorito, KB Kuchenbaecker, J Beesley, J Adlard, BA Agnarsson, IL Andrulis, BK Arun, L Barjhoux, M Belotti, J Benitez, et al. (2016) PLOS ONE. 11(7).
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 BRCA2 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 2x 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 x 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
BREAST, INVESTIGATORS, SUSCEPTIBILITY LOCI, GENOME-WIDE ASSOCIATION, CONSORTIUM, PATHOLOGY, CENTLEIN
journal title
PLOS ONE
PLoS One
volume
11
issue
7
article number
e0158801
pages
19 pages
Web of Science type
Article
Web of Science id
000381515900021
JCR category
MULTIDISCIPLINARY SCIENCES
JCR impact factor
2.806 (2016)
JCR rank
15/64 (2016)
JCR quartile
1 (2016)
ISSN
1932-6203
DOI
10.1371/journal.pone.0158801
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
8120163
handle
http://hdl.handle.net/1854/LU-8120163
date created
2016-10-19 14:14:25
date last changed
2017-03-07 12:09:17
@article{8120163,
  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 BRCA2 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 2x 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 x 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.},
  articleno    = {e0158801},
  author       = {Vigorito, E and Kuchenbaecker, KB and Beesley, J and Adlard, J and Agnarsson, BA and Andrulis, IL and Arun, BK and Barjhoux, L and Belotti, M and Benitez, J and Berger, A and Bojesen, A and Bonanni, B and Brewer, C and Caldes, T and Caligo, MA and Campbell, I and Chan, SB and Claes, Kathleen and Cohn, DE and Cook, J and Daly, MB and Damiola, F and Davidson, R and de Pauw, A and Delnatte, C and Diez, O and Domchek, SM and Dumont, M and Durda, K and Dworniczak, B and Easton, DF and Eccles, D and Ardnor, CE and Eeles, R and Ejlertsen, B and Ellis, S and Evans, DG and Feliubadalo, L and Fostira, F and Foulkes, WD and Friedman, E and Frost, D and Gaddam, P and Ganz, PA and Garber, J and Garcia-Barberan, V and Gauthier-Villars, M and Gehrig, A and Gerdes, AM and Giraud, S and Godwin, AK and Goldgar, DE and Hake, CR and Hansen, TVO and Healey, S and Hodgson, S and Hogervorst, FBL and Houdayer, C and Hulick, PJ and Imyanitov, EN and Isaacs, C and Izatt, L and Izquierdo, A and Jacobs, L and Jakubowska, A and Janavicius, R and Jaworska-Bieniek, K and Jensen, UB and John, EM and Vijai, J and Karlan, BY and Kast, K and Khan, S and Kwong, A and Laitman, Y and Lester, J and Lesueur, F and Liljegren, A and Lubinski, J and Mai, PL and Manoukian, S and Mazoyer, S and Meindl, A and Mensenkamp, AR and Montagna, M and Nathanson, KL and Neuhausen, SL and Nevanlinna, H and Niederacher, D and Olah, E and Olopade, OI and Ong, KR and Osorio, A and Park, SK and Paulsson-Karlsson, Y and Pedersen, IS and Peissel, B and Peterlongo, P and Pfeiler, G and Phelan, CM and Piedmonte, M and Poppe, Bruce and Pujana, MA and Radice, P and Rennert, G and Rodriguez, GC and Rookus, MA and Ross, EA and Schmutzler, RK and Simard, J and Singer, CF and Slavin, TP and Soucy, P and Southey, M and Steinemann, D and Stoppa-Lyonnet, D and Sukiennicki, G and Sutter, C and Szabo, CI and Tea, MK and Teixeira, MR and Teo, SH and Terry, MB and Thomassen, M and Tibiletti, MG and Tihomirova, L and Tognazzo, S and van Rensburg, EJ and Varesco, L and Varon-Mateeva, R and Vratimos, A and Weitzel, JN and McGuffog, L and Kirk, J and Toland, AE and Hamann, U and Lindor, N and Ramus, SJ and Greene, MH and Couch, FJ and Offit, K and Pharoah, PDP and Chenevix-Trench, G and Antoniou, AC},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keyword      = {BREAST,INVESTIGATORS,SUSCEPTIBILITY LOCI,GENOME-WIDE ASSOCIATION,CONSORTIUM,PATHOLOGY,CENTLEIN},
  language     = {eng},
  number       = {7},
  pages        = {19},
  title        = {Fine-scale mapping at 9p22.2 identifies candidate causal variants that modify ovarian cancer risk in BRCA1 and BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1371/journal.pone.0158801},
  volume       = {11},
  year         = {2016},
}

Chicago
Vigorito, E, KB Kuchenbaecker, J Beesley, J Adlard, BA Agnarsson, IL Andrulis, BK Arun, et al. 2016. “Fine-scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.” Plos One 11 (7).
APA
Vigorito, E., Kuchenbaecker, K., Beesley, J., Adlard, J., Agnarsson, B., Andrulis, I., Arun, B., et al. (2016). Fine-scale mapping at 9p22.2 identifies candidate causal variants that modify ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. PLOS ONE, 11(7).
Vancouver
1.
Vigorito E, Kuchenbaecker K, Beesley J, Adlard J, Agnarsson B, Andrulis I, et al. Fine-scale mapping at 9p22.2 identifies candidate causal variants that modify ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. PLOS ONE. 2016;11(7).
MLA
Vigorito, E, KB Kuchenbaecker, J Beesley, et al. “Fine-scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.” PLOS ONE 11.7 (2016): n. pag. Print.