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

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)e0158801
JournalPLoS One
Volume11
Issue number7
DOIs
StatePublished - Jan 1 2016

Fingerprint

ovarian neoplasms
Ovarian Neoplasms
mutation
Mutation
Single Nucleotide Polymorphism
Transcription Initiation Site
Population
Genes
Genotype
loci
genotype
Genome-Wide Association Study
transcription (genetics)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Vigorito, E., Kuchenbaecker, K. B., Beesley, J., Adlard, J., Agnarsson, B. A., Andrulis, I. L., ... Antoniou, A. C. (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), e0158801. https://doi.org/10.1371/journal.pone.0158801

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; Evans, D. Gareth; Feliubadalo, 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, KCon Fab; 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 Morey; Ramus, Susan J.; Greene, Mark H.; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

In: PLoS One, Vol. 11, No. 7, 01.01.2016, p. e0158801.

Research output: Contribution to journalArticle

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, AM, 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, Investigators, KCF, 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, KR, 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, MK, Teixeira, MR, Teo, SH, 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, NM, Ramus, SJ, Greene, MH, Couch, FJ, Offit, K, Pharoah, PDP, Chenevix-Trench, G & Antoniou, AC 2016, 'Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers', PLoS One, vol. 11, no. 7, pp. e0158801. https://doi.org/10.1371/journal.pone.0158801
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 ; Evans, D. Gareth ; Feliubadalo, 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, KCon Fab ; 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 Morey ; Ramus, Susan J. ; Greene, Mark H. ; Couch, Fergus J ; Offit, Kenneth ; Pharoah, Paul D.P. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. / Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. In: PLoS One. 2016 ; Vol. 11, No. 7. pp. e0158801.
@article{7beca3f450304c2bbb7184fa44f0747e,
title = "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.",
author = "Elena Vigorito and Kuchenbaecker, {Karoline B.} and Jonathan Beesley and Julian Adlard and Agnarsson, {Bjarni A.} and Andrulis, {Irene L.} and Arun, {Banu K.} and Laure Barjhoux and Muriel Belotti and Javier Benitez and Andreas Berger and Anders Bojesen and Bernardo Bonanni and Carole Brewer and Trinidad Caldes and Caligo, {Maria A.} and Ian Campbell and Chan, {Salina B.} and Claes, {Kathleen B.M.} and Cohn, {David E.} and Jackie Cook and Daly, {Mary B.} and Francesca Damiola and Rosemarie Davidson and Pauw, {Antoine de} and Capucine Delnatte and Orland Diez and Domchek, {Susan M.} and Martine Dumont and Katarzyna Durda and Bernd Dworniczak and Easton, {Douglas F.} and Diana Eccles and {Edwinsdotter Ardnor}, Christina and Ros Eeles and Bent Ejlertsen and Steve Ellis and Evans, {D. Gareth} and Lidia Feliubadalo and Florentia Fostira and Foulkes, {William D.} and Eitan Friedman and Debra Frost and Pragna Gaddam and Ganz, {Patricia A.} and Judy Garber and Vanesa Garcia-Barberan and Marion Gauthier-Villars and Andrea Gehrig and Gerdes, {Anne Marie} and Sophie Giraud and Godwin, {Andrew K.} and Goldgar, {David E.} and Hake, {Christopher R.} and Hansen, {Thomas V.O.} and Sue Healey and Shirley Hodgson and Hogervorst, {Frans B.L.} and Claude Houdayer and Hulick, {Peter J.} and Imyanitov, {Evgeny N.} and Claudine Isaacs and Louise Izatt and Angel Izquierdo and Lauren Jacobs and Anna Jakubowska and Ramunas Janavicius and Katarzyna Jaworska-Bieniek and Jensen, {Uffe Birk} and John, {Esther M.} and Joseph Vijai and Karlan, {Beth Y.} and Karin Kast and Investigators, {KCon Fab} and Sofia Khan and Ava Kwong and Yael Laitman and Jenny Lester and Fabienne Lesueur and Annelie Liljegren and Jan Lubinski and Mai, {Phuong L.} and Siranoush Manoukian and Sylvie Mazoyer and Alfons Meindl and Mensenkamp, {Arjen R.} and Marco Montagna and Nathanson, {Katherine L.} and Neuhausen, {Susan L.} and Heli Nevanlinna and Dieter Niederacher and Edith Olah and Olopade, {Olufunmilayo I.} and Ong, {Kai Ren} and Ana Osorio and Park, {Sue Kyung} and Ylva Paulsson-Karlsson and Pedersen, {Inge Sokilde} and Bernard Peissel and Paolo Peterlongo and Georg Pfeiler and Phelan, {Catherine M.} and Marion Piedmonte and Bruce Poppe and Pujana, {Miquel Angel} and Paolo Radice and Gad Rennert and Rodriguez, {Gustavo C.} and Rookus, {Matti A.} and Ross, {Eric A.} and Schmutzler, {Rita Katharina} and Jacques Simard and Singer, {Christian F.} and Slavin, {Thomas P.} and Penny Soucy and Melissa Southey and Doris Steinemann and Dominique Stoppa-Lyonnet and Grzegorz Sukiennicki and Christian Sutter and Szabo, {Csilla I.} and Tea, {Muy Kheng} and Teixeira, {Manuel R.} and Teo, {Soo Hwang} and Terry, {Mary Beth} and Mads Thomassen and Tibiletti, {Maria Grazia} and Laima Tihomirova and Silvia Tognazzo and {van Rensburg}, {Elizabeth J.} and Liliana Varesco and Raymonda Varon-Mateeva and Athanassios Vratimos and Weitzel, {Jeffrey N.} and Lesley McGuffog and Judy Kirk and Toland, {Amanda Ewart} and Ute Hamann and Lindor, {Noralane Morey} and Ramus, {Susan J.} and Greene, {Mark H.} and Couch, {Fergus J} and Kenneth Offit and Pharoah, {Paul D.P.} and Georgia Chenevix-Trench and Antoniou, {Antonis C.}",
year = "2016",
month = "1",
day = "1",
doi = "10.1371/journal.pone.0158801",
language = "English (US)",
volume = "11",
pages = "e0158801",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

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

AU - Evans, D. Gareth

AU - Feliubadalo, 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, KCon Fab

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 Morey

AU - Ramus, Susan J.

AU - Greene, Mark H.

AU - Couch, Fergus J

AU - Offit, Kenneth

AU - Pharoah, Paul D.P.

AU - Chenevix-Trench, Georgia

AU - Antoniou, Antonis C.

PY - 2016/1/1

Y1 - 2016/1/1

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.

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U2 - 10.1371/journal.pone.0158801

DO - 10.1371/journal.pone.0158801

M3 - Article

C2 - 27463617

AN - SCOPUS:85016937957

VL - 11

SP - e0158801

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

ER -