Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation ca...

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Autores principales:	Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M Sinilnikova, Vernon S Pankratz, Xianshu Wang, Ronald C Eldridge, Daniel C Tessier, Daniel Vincent, Francois Bacot, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, KConFab Investigators, Paolo Peterlongo, Rita K Schmutzler, Katherine L Nathanson, Marion Piedmonte, Christian F Singer, Mads Thomassen, Ontario Cancer Genetics Network, Thomas v O Hansen, Susan L Neuhausen, Ignacio Blanco, Mark H Greene, Judith Garber, Jeffrey N Weitzel, Irene L Andrulis, David E Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H van der Hout, Carolien M Kets, Cora M Aalfs, Juul T Wijnen, Margreet G E M Ausems, HEBON, EMBRACE, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E Porteous, Francesca Damiola, GEMO Study Collaborators, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L Mai, Javier Benitez, Melissa C Southey, Marjanka K Schmidt, Peter A Fasching, Julian Peto, Manjeet K Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E Bojesen, Roger L Milne, Hermann Brenner, Magdalena Lochmann, GENICA Network, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G Giles, Christopher A Haiman, Robert Winqvist, Peter Devillee, Montserrat García-Closas, Nils Schoof, Maartje J Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Kenneth Offit
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/f45b7c806857476fa2644c704c807fc3
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id	oai:doaj.org-article:f45b7c806857476fa2644c704c807fc3
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Mia M Gaudet Karoline B Kuchenbaecker Joseph Vijai Robert J Klein Tomas Kirchhoff Lesley McGuffog Daniel Barrowdale Alison M Dunning Andrew Lee Joe Dennis Sue Healey Ed Dicks Penny Soucy Olga M Sinilnikova Vernon S Pankratz Xianshu Wang Ronald C Eldridge Daniel C Tessier Daniel Vincent Francois Bacot Frans B L Hogervorst Susan Peock Dominique Stoppa-Lyonnet KConFab Investigators Paolo Peterlongo Rita K Schmutzler Katherine L Nathanson Marion Piedmonte Christian F Singer Mads Thomassen Ontario Cancer Genetics Network Thomas v O Hansen Susan L Neuhausen Ignacio Blanco Mark H Greene Judith Garber Jeffrey N Weitzel Irene L Andrulis David E Goldgar Emma D'Andrea Trinidad Caldes Heli Nevanlinna Ana Osorio Elizabeth J van Rensburg Adalgeir Arason Gad Rennert Ans M W van den Ouweland Annemarie H van der Hout Carolien M Kets Cora M Aalfs Juul T Wijnen Margreet G E M Ausems HEBON EMBRACE Debra Frost Steve Ellis Elena Fineberg Radka Platte D Gareth Evans Chris Jacobs Julian Adlard Marc Tischkowitz Mary E Porteous Francesca Damiola GEMO Study Collaborators Lisa Golmard Laure Barjhoux Michel Longy Muriel Belotti Sandra Fert Ferrer Sylvie Mazoyer Amanda B Spurdle Siranoush Manoukian Monica Barile Maurizio Genuardi Norbert Arnold Alfons Meindl Christian Sutter Barbara Wappenschmidt Susan M Domchek Georg Pfeiler Eitan Friedman Uffe Birk Jensen Mark Robson Sohela Shah Conxi Lazaro Phuong L Mai Javier Benitez Melissa C Southey Marjanka K Schmidt Peter A Fasching Julian Peto Manjeet K Humphreys Qin Wang Kyriaki Michailidou Elinor J Sawyer Barbara Burwinkel Pascal Guénel Stig E Bojesen Roger L Milne Hermann Brenner Magdalena Lochmann GENICA Network Kristiina Aittomäki Thilo Dörk Sara Margolin Arto Mannermaa Diether Lambrechts Jenny Chang-Claude Paolo Radice Graham G Giles Christopher A Haiman Robert Winqvist Peter Devillee Montserrat García-Closas Nils Schoof Maartje J Hooning Angela Cox Paul D P Pharoah Anna Jakubowska Nick Orr Anna González-Neira Guillermo Pita M Rosario Alonso Per Hall Fergus J Couch Jacques Simard David Altshuler Douglas F Easton Georgia Chenevix-Trench Antonis C Antoniou Kenneth Offit Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.
description	Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
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author	Mia M Gaudet Karoline B Kuchenbaecker Joseph Vijai Robert J Klein Tomas Kirchhoff Lesley McGuffog Daniel Barrowdale Alison M Dunning Andrew Lee Joe Dennis Sue Healey Ed Dicks Penny Soucy Olga M Sinilnikova Vernon S Pankratz Xianshu Wang Ronald C Eldridge Daniel C Tessier Daniel Vincent Francois Bacot Frans B L Hogervorst Susan Peock Dominique Stoppa-Lyonnet KConFab Investigators Paolo Peterlongo Rita K Schmutzler Katherine L Nathanson Marion Piedmonte Christian F Singer Mads Thomassen Ontario Cancer Genetics Network Thomas v O Hansen Susan L Neuhausen Ignacio Blanco Mark H Greene Judith Garber Jeffrey N Weitzel Irene L Andrulis David E Goldgar Emma D'Andrea Trinidad Caldes Heli Nevanlinna Ana Osorio Elizabeth J van Rensburg Adalgeir Arason Gad Rennert Ans M W van den Ouweland Annemarie H van der Hout Carolien M Kets Cora M Aalfs Juul T Wijnen Margreet G E M Ausems HEBON EMBRACE Debra Frost Steve Ellis Elena Fineberg Radka Platte D Gareth Evans Chris Jacobs Julian Adlard Marc Tischkowitz Mary E Porteous Francesca Damiola GEMO Study Collaborators Lisa Golmard Laure Barjhoux Michel Longy Muriel Belotti Sandra Fert Ferrer Sylvie Mazoyer Amanda B Spurdle Siranoush Manoukian Monica Barile Maurizio Genuardi Norbert Arnold Alfons Meindl Christian Sutter Barbara Wappenschmidt Susan M Domchek Georg Pfeiler Eitan Friedman Uffe Birk Jensen Mark Robson Sohela Shah Conxi Lazaro Phuong L Mai Javier Benitez Melissa C Southey Marjanka K Schmidt Peter A Fasching Julian Peto Manjeet K Humphreys Qin Wang Kyriaki Michailidou Elinor J Sawyer Barbara Burwinkel Pascal Guénel Stig E Bojesen Roger L Milne Hermann Brenner Magdalena Lochmann GENICA Network Kristiina Aittomäki Thilo Dörk Sara Margolin Arto Mannermaa Diether Lambrechts Jenny Chang-Claude Paolo Radice Graham G Giles Christopher A Haiman Robert Winqvist Peter Devillee Montserrat García-Closas Nils Schoof Maartje J Hooning Angela Cox Paul D P Pharoah Anna Jakubowska Nick Orr Anna González-Neira Guillermo Pita M Rosario Alonso Per Hall Fergus J Couch Jacques Simard David Altshuler Douglas F Easton Georgia Chenevix-Trench Antonis C Antoniou Kenneth Offit
author_facet	Mia M Gaudet Karoline B Kuchenbaecker Joseph Vijai Robert J Klein Tomas Kirchhoff Lesley McGuffog Daniel Barrowdale Alison M Dunning Andrew Lee Joe Dennis Sue Healey Ed Dicks Penny Soucy Olga M Sinilnikova Vernon S Pankratz Xianshu Wang Ronald C Eldridge Daniel C Tessier Daniel Vincent Francois Bacot Frans B L Hogervorst Susan Peock Dominique Stoppa-Lyonnet KConFab Investigators Paolo Peterlongo Rita K Schmutzler Katherine L Nathanson Marion Piedmonte Christian F Singer Mads Thomassen Ontario Cancer Genetics Network Thomas v O Hansen Susan L Neuhausen Ignacio Blanco Mark H Greene Judith Garber Jeffrey N Weitzel Irene L Andrulis David E Goldgar Emma D'Andrea Trinidad Caldes Heli Nevanlinna Ana Osorio Elizabeth J van Rensburg Adalgeir Arason Gad Rennert Ans M W van den Ouweland Annemarie H van der Hout Carolien M Kets Cora M Aalfs Juul T Wijnen Margreet G E M Ausems HEBON EMBRACE Debra Frost Steve Ellis Elena Fineberg Radka Platte D Gareth Evans Chris Jacobs Julian Adlard Marc Tischkowitz Mary E Porteous Francesca Damiola GEMO Study Collaborators Lisa Golmard Laure Barjhoux Michel Longy Muriel Belotti Sandra Fert Ferrer Sylvie Mazoyer Amanda B Spurdle Siranoush Manoukian Monica Barile Maurizio Genuardi Norbert Arnold Alfons Meindl Christian Sutter Barbara Wappenschmidt Susan M Domchek Georg Pfeiler Eitan Friedman Uffe Birk Jensen Mark Robson Sohela Shah Conxi Lazaro Phuong L Mai Javier Benitez Melissa C Southey Marjanka K Schmidt Peter A Fasching Julian Peto Manjeet K Humphreys Qin Wang Kyriaki Michailidou Elinor J Sawyer Barbara Burwinkel Pascal Guénel Stig E Bojesen Roger L Milne Hermann Brenner Magdalena Lochmann GENICA Network Kristiina Aittomäki Thilo Dörk Sara Margolin Arto Mannermaa Diether Lambrechts Jenny Chang-Claude Paolo Radice Graham G Giles Christopher A Haiman Robert Winqvist Peter Devillee Montserrat García-Closas Nils Schoof Maartje J Hooning Angela Cox Paul D P Pharoah Anna Jakubowska Nick Orr Anna González-Neira Guillermo Pita M Rosario Alonso Per Hall Fergus J Couch Jacques Simard David Altshuler Douglas F Easton Georgia Chenevix-Trench Antonis C Antoniou Kenneth Offit
author_sort	Mia M Gaudet
title	Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.
title_short	Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.
title_full	Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.
title_fullStr	Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.
title_full_unstemmed	Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.
title_sort	identification of a brca2-specific modifier locus at 6p24 related to breast cancer risk.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/f45b7c806857476fa2644c704c807fc3
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spelling	oai:doaj.org-article:f45b7c806857476fa2644c704c807fc32021-11-18T06:19:53ZIdentification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.1553-73901553-740410.1371/journal.pgen.1003173https://doaj.org/article/f45b7c806857476fa2644c704c807fc32013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23544012/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.Mia M GaudetKaroline B KuchenbaeckerJoseph VijaiRobert J KleinTomas KirchhoffLesley McGuffogDaniel BarrowdaleAlison M DunningAndrew LeeJoe DennisSue HealeyEd DicksPenny SoucyOlga M SinilnikovaVernon S PankratzXianshu WangRonald C EldridgeDaniel C TessierDaniel VincentFrancois BacotFrans B L HogervorstSusan PeockDominique Stoppa-LyonnetKConFab InvestigatorsPaolo PeterlongoRita K SchmutzlerKatherine L NathansonMarion PiedmonteChristian F SingerMads ThomassenOntario Cancer Genetics NetworkThomas v O HansenSusan L NeuhausenIgnacio BlancoMark H GreeneJudith GarberJeffrey N WeitzelIrene L AndrulisDavid E GoldgarEmma D'AndreaTrinidad CaldesHeli NevanlinnaAna OsorioElizabeth J van RensburgAdalgeir ArasonGad RennertAns M W van den OuwelandAnnemarie H van der HoutCarolien M KetsCora M AalfsJuul T WijnenMargreet G E M AusemsHEBONEMBRACEDebra FrostSteve EllisElena FinebergRadka PlatteD Gareth EvansChris JacobsJulian AdlardMarc TischkowitzMary E PorteousFrancesca DamiolaGEMO Study CollaboratorsLisa GolmardLaure BarjhouxMichel LongyMuriel BelottiSandra Fert FerrerSylvie MazoyerAmanda B SpurdleSiranoush ManoukianMonica BarileMaurizio GenuardiNorbert ArnoldAlfons MeindlChristian SutterBarbara WappenschmidtSusan M DomchekGeorg PfeilerEitan FriedmanUffe Birk JensenMark RobsonSohela ShahConxi LazaroPhuong L MaiJavier BenitezMelissa C SoutheyMarjanka K SchmidtPeter A FaschingJulian PetoManjeet K HumphreysQin WangKyriaki MichailidouElinor J SawyerBarbara BurwinkelPascal GuénelStig E BojesenRoger L MilneHermann BrennerMagdalena LochmannGENICA NetworkKristiina AittomäkiThilo DörkSara MargolinArto MannermaaDiether LambrechtsJenny Chang-ClaudePaolo RadiceGraham G GilesChristopher A HaimanRobert WinqvistPeter DevilleeMontserrat García-ClosasNils SchoofMaartje J HooningAngela CoxPaul D P PharoahAnna JakubowskaNick OrrAnna González-NeiraGuillermo PitaM Rosario AlonsoPer HallFergus J CouchJacques SimardDavid AltshulerDouglas F EastonGeorgia Chenevix-TrenchAntonis C AntoniouKenneth OffitPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 9, Iss 3, p e1003173 (2013)

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

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