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.
| Original language | English |
|---|---|
| Article number | e0158801 |
| Journal | PLoS ONE |
| Volume | 11 |
| Issue number | 7 |
| Number of pages | 19 |
| ISSN | 1932-6203 |
| DOIs | |
| Publication status | Published - 2016 |
Keywords
- Journal Article
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- 10.1371/journal.pone.0158801Licence: CC0
- Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation CarriersFinal published version, 1.8 MBLicence: CC0
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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; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve D; Evans, D Gareth; Feliubadaló, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas v O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, Kconfab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary-Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul P D; Chenevix-Trench, Georgia; Antoniou, Antonis C.
In: PLoS ONE, Vol. 11, No. 7, e0158801, 2016.Research output: Contribution to journal › Journal article › Research › peer-review
}
TY - JOUR
T1 - Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
AU - Vigorito, Elena
AU - Kuchenbaecker, Karoline B
AU - Beesley, Jonathan
AU - Adlard, Julian
AU - Agnarsson, Bjarni A
AU - Andrulis, Irene L
AU - Arun, Banu K
AU - Barjhoux, Laure
AU - Belotti, Muriel
AU - Benitez, Javier
AU - Berger, Andreas
AU - Bojesen, Anders
AU - Bonanni, Bernardo
AU - Brewer, Carole
AU - Caldes, Trinidad
AU - Caligo, Maria A
AU - Campbell, Ian
AU - Chan, Salina B
AU - Claes, Kathleen B M
AU - Cohn, David E
AU - Cook, Jackie
AU - Daly, Mary B
AU - Damiola, Francesca
AU - Davidson, Rosemarie
AU - Pauw, Antoine de
AU - Delnatte, Capucine
AU - Diez, Orland
AU - Domchek, Susan M
AU - Dumont, Martine
AU - Durda, Katarzyna
AU - Dworniczak, Bernd
AU - Easton, Douglas F
AU - Eccles, Diana
AU - Edwinsdotter Ardnor, Christina
AU - Eeles, Ros
AU - Ejlertsen, Bent
AU - Ellis, Steve D
AU - Evans, D Gareth
AU - Feliubadaló, Lidia
AU - Fostira, Florentia
AU - Foulkes, William D
AU - Friedman, Eitan
AU - Frost, Debra
AU - Gaddam, Pragna
AU - Ganz, Patricia A
AU - Garber, Judy
AU - Garcia-Barberan, Vanesa
AU - Gauthier-Villars, Marion
AU - Gehrig, Andrea
AU - Gerdes, Anne-Marie
AU - Giraud, Sophie
AU - Godwin, Andrew K
AU - Goldgar, David E
AU - Hake, Christopher R
AU - Hansen, Thomas v O
AU - Healey, Sue
AU - Hodgson, Shirley
AU - Hogervorst, Frans B L
AU - Houdayer, Claude
AU - Hulick, Peter J
AU - Imyanitov, Evgeny N
AU - Isaacs, Claudine
AU - Izatt, Louise
AU - Izquierdo, Angel
AU - Jacobs, Lauren
AU - Jakubowska, Anna
AU - Janavicius, Ramunas
AU - Jaworska-Bieniek, Katarzyna
AU - Jensen, Uffe Birk
AU - John, Esther M
AU - Vijai, Joseph
AU - Karlan, Beth Y
AU - Kast, Karin
AU - Investigators, Kconfab
AU - Khan, Sofia
AU - Kwong, Ava
AU - Laitman, Yael
AU - Lester, Jenny
AU - Lesueur, Fabienne
AU - Liljegren, Annelie
AU - Lubinski, Jan
AU - Mai, Phuong L
AU - Manoukian, Siranoush
AU - Mazoyer, Sylvie
AU - Meindl, Alfons
AU - Mensenkamp, Arjen R
AU - Montagna, Marco
AU - Nathanson, Katherine L
AU - Neuhausen, Susan L
AU - Nevanlinna, Heli
AU - Niederacher, Dieter
AU - Olah, Edith
AU - Olopade, Olufunmilayo I
AU - Ong, Kai-ren
AU - Osorio, Ana
AU - Park, Sue Kyung
AU - Paulsson-Karlsson, Ylva
AU - Pedersen, Inge Sokilde
AU - Peissel, Bernard
AU - Peterlongo, Paolo
AU - Pfeiler, Georg
AU - Phelan, Catherine M
AU - Piedmonte, Marion
AU - Poppe, Bruce
AU - Pujana, Miquel Angel
AU - Radice, Paolo
AU - Rennert, Gad
AU - Rodriguez, Gustavo C
AU - Rookus, Matti A
AU - Ross, Eric A
AU - Schmutzler, Rita Katharina
AU - Simard, Jacques
AU - Singer, Christian F
AU - Slavin, Thomas P
AU - Soucy, Penny
AU - Southey, Melissa
AU - Steinemann, Doris
AU - Stoppa-Lyonnet, Dominique
AU - Sukiennicki, Grzegorz
AU - Sutter, Christian
AU - Szabo, Csilla I
AU - Tea, Muy-Kheng
AU - Teixeira, Manuel R
AU - Teo, Soo-Hwang
AU - Terry, Mary-Beth
AU - Thomassen, Mads
AU - Tibiletti, Maria Grazia
AU - Tihomirova, Laima
AU - Tognazzo, Silvia
AU - van Rensburg, Elizabeth J
AU - Varesco, Liliana
AU - Varon-Mateeva, Raymonda
AU - Vratimos, Athanassios
AU - Weitzel, Jeffrey N
AU - McGuffog, Lesley
AU - Kirk, Judy
AU - Toland, Amanda Ewart
AU - Hamann, Ute
AU - Lindor, Noralane
AU - Ramus, Susan J
AU - Greene, Mark H
AU - Couch, Fergus J
AU - Offit, Kenneth
AU - Pharoah, Paul P D
AU - Chenevix-Trench, Georgia
AU - Antoniou, Antonis C
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1371/journal.pone.0158801
DO - 10.1371/journal.pone.0158801
M3 - Journal article
C2 - 27463617
VL - 11
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 7
M1 - e0158801
ER -