Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers...
Guardado en:
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
Public Library of Science (PLoS)
2010
|
Materias: | |
Acceso en línea: | https://doaj.org/article/c7a705a431ab474c952a747fa473b1e8 |
Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
id |
oai:doaj.org-article:c7a705a431ab474c952a747fa473b1e8 |
---|---|
record_format |
dspace |
institution |
DOAJ |
collection |
DOAJ |
language |
EN |
topic |
Genetics QH426-470 |
spellingShingle |
Genetics QH426-470 Mia M Gaudet Tomas Kirchhoff Todd Green Joseph Vijai Joshua M Korn Candace Guiducci Ayellet V Segrè Kate McGee Lesley McGuffog Christiana Kartsonaki Jonathan Morrison Sue Healey Olga M Sinilnikova Dominique Stoppa-Lyonnet Sylvie Mazoyer Marion Gauthier-Villars Hagay Sobol Michel Longy Marc Frenay GEMO Study Collaborators Frans B L Hogervorst Matti A Rookus J Margriet Collée Nicoline Hoogerbrugge Kees E P van Roozendaal HEBON Study Collaborators Marion Piedmonte Wendy Rubinstein Stacy Nerenstone Linda Van Le Stephanie V Blank Trinidad Caldés Miguel de la Hoya Heli Nevanlinna Kristiina Aittomäki Conxi Lazaro Ignacio Blanco Adalgeir Arason Oskar T Johannsson Rosa B Barkardottir Peter Devilee Olofunmilayo I Olopade Susan L Neuhausen Xianshu Wang Zachary S Fredericksen Paolo Peterlongo Siranoush Manoukian Monica Barile Alessandra Viel Paolo Radice Catherine M Phelan Steven Narod Gad Rennert Flavio Lejbkowicz Anath Flugelman Irene L Andrulis Gord Glendon Hilmi Ozcelik OCGN Amanda E Toland Marco Montagna Emma D'Andrea Eitan Friedman Yael Laitman Ake Borg Mary Beattie Susan J Ramus Susan M Domchek Katherine L Nathanson Tim Rebbeck Amanda B Spurdle Xiaoqing Chen Helene Holland kConFab Esther M John John L Hopper Saundra S Buys Mary B Daly Melissa C Southey Mary Beth Terry Nadine Tung Thomas V Overeem Hansen Finn C Nielsen Mark H Greene Phuong L Mai Ana Osorio Mercedes Durán Raquel Andres Javier Benítez Jeffrey N Weitzel Judy Garber Ute Hamann EMBRACE Susan Peock Margaret Cook Clare Oliver Debra Frost Radka Platte D Gareth Evans Fiona Lalloo Ros Eeles Louise Izatt Lisa Walker Jacqueline Eason Julian Barwell Andrew K Godwin Rita K Schmutzler Barbara Wappenschmidt Stefanie Engert Norbert Arnold Dorothea Gadzicki Michael Dean Bert Gold Robert J Klein Fergus J Couch Georgia Chenevix-Trench Douglas F Easton Mark J Daly Antonis C Antoniou David M Altshuler Kenneth Offit Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. |
description |
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. |
format |
article |
author |
Mia M Gaudet Tomas Kirchhoff Todd Green Joseph Vijai Joshua M Korn Candace Guiducci Ayellet V Segrè Kate McGee Lesley McGuffog Christiana Kartsonaki Jonathan Morrison Sue Healey Olga M Sinilnikova Dominique Stoppa-Lyonnet Sylvie Mazoyer Marion Gauthier-Villars Hagay Sobol Michel Longy Marc Frenay GEMO Study Collaborators Frans B L Hogervorst Matti A Rookus J Margriet Collée Nicoline Hoogerbrugge Kees E P van Roozendaal HEBON Study Collaborators Marion Piedmonte Wendy Rubinstein Stacy Nerenstone Linda Van Le Stephanie V Blank Trinidad Caldés Miguel de la Hoya Heli Nevanlinna Kristiina Aittomäki Conxi Lazaro Ignacio Blanco Adalgeir Arason Oskar T Johannsson Rosa B Barkardottir Peter Devilee Olofunmilayo I Olopade Susan L Neuhausen Xianshu Wang Zachary S Fredericksen Paolo Peterlongo Siranoush Manoukian Monica Barile Alessandra Viel Paolo Radice Catherine M Phelan Steven Narod Gad Rennert Flavio Lejbkowicz Anath Flugelman Irene L Andrulis Gord Glendon Hilmi Ozcelik OCGN Amanda E Toland Marco Montagna Emma D'Andrea Eitan Friedman Yael Laitman Ake Borg Mary Beattie Susan J Ramus Susan M Domchek Katherine L Nathanson Tim Rebbeck Amanda B Spurdle Xiaoqing Chen Helene Holland kConFab Esther M John John L Hopper Saundra S Buys Mary B Daly Melissa C Southey Mary Beth Terry Nadine Tung Thomas V Overeem Hansen Finn C Nielsen Mark H Greene Phuong L Mai Ana Osorio Mercedes Durán Raquel Andres Javier Benítez Jeffrey N Weitzel Judy Garber Ute Hamann EMBRACE Susan Peock Margaret Cook Clare Oliver Debra Frost Radka Platte D Gareth Evans Fiona Lalloo Ros Eeles Louise Izatt Lisa Walker Jacqueline Eason Julian Barwell Andrew K Godwin Rita K Schmutzler Barbara Wappenschmidt Stefanie Engert Norbert Arnold Dorothea Gadzicki Michael Dean Bert Gold Robert J Klein Fergus J Couch Georgia Chenevix-Trench Douglas F Easton Mark J Daly Antonis C Antoniou David M Altshuler Kenneth Offit |
author_facet |
Mia M Gaudet Tomas Kirchhoff Todd Green Joseph Vijai Joshua M Korn Candace Guiducci Ayellet V Segrè Kate McGee Lesley McGuffog Christiana Kartsonaki Jonathan Morrison Sue Healey Olga M Sinilnikova Dominique Stoppa-Lyonnet Sylvie Mazoyer Marion Gauthier-Villars Hagay Sobol Michel Longy Marc Frenay GEMO Study Collaborators Frans B L Hogervorst Matti A Rookus J Margriet Collée Nicoline Hoogerbrugge Kees E P van Roozendaal HEBON Study Collaborators Marion Piedmonte Wendy Rubinstein Stacy Nerenstone Linda Van Le Stephanie V Blank Trinidad Caldés Miguel de la Hoya Heli Nevanlinna Kristiina Aittomäki Conxi Lazaro Ignacio Blanco Adalgeir Arason Oskar T Johannsson Rosa B Barkardottir Peter Devilee Olofunmilayo I Olopade Susan L Neuhausen Xianshu Wang Zachary S Fredericksen Paolo Peterlongo Siranoush Manoukian Monica Barile Alessandra Viel Paolo Radice Catherine M Phelan Steven Narod Gad Rennert Flavio Lejbkowicz Anath Flugelman Irene L Andrulis Gord Glendon Hilmi Ozcelik OCGN Amanda E Toland Marco Montagna Emma D'Andrea Eitan Friedman Yael Laitman Ake Borg Mary Beattie Susan J Ramus Susan M Domchek Katherine L Nathanson Tim Rebbeck Amanda B Spurdle Xiaoqing Chen Helene Holland kConFab Esther M John John L Hopper Saundra S Buys Mary B Daly Melissa C Southey Mary Beth Terry Nadine Tung Thomas V Overeem Hansen Finn C Nielsen Mark H Greene Phuong L Mai Ana Osorio Mercedes Durán Raquel Andres Javier Benítez Jeffrey N Weitzel Judy Garber Ute Hamann EMBRACE Susan Peock Margaret Cook Clare Oliver Debra Frost Radka Platte D Gareth Evans Fiona Lalloo Ros Eeles Louise Izatt Lisa Walker Jacqueline Eason Julian Barwell Andrew K Godwin Rita K Schmutzler Barbara Wappenschmidt Stefanie Engert Norbert Arnold Dorothea Gadzicki Michael Dean Bert Gold Robert J Klein Fergus J Couch Georgia Chenevix-Trench Douglas F Easton Mark J Daly Antonis C Antoniou David M Altshuler Kenneth Offit |
author_sort |
Mia M Gaudet |
title |
Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. |
title_short |
Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. |
title_full |
Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. |
title_fullStr |
Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. |
title_full_unstemmed |
Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. |
title_sort |
common genetic variants and modification of penetrance of brca2-associated breast cancer. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2010 |
url |
https://doaj.org/article/c7a705a431ab474c952a747fa473b1e8 |
work_keys_str_mv |
AT miamgaudet commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT tomaskirchhoff commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT toddgreen commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT josephvijai commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT joshuamkorn commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT candaceguiducci commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT ayelletvsegre commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT katemcgee commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT lesleymcguffog commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT christianakartsonaki commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT jonathanmorrison commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT suehealey commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT olgamsinilnikova commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT dominiquestoppalyonnet commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT sylviemazoyer commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT mariongauthiervillars commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT hagaysobol commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT michellongy commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT marcfrenay commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT gemostudycollaborators commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT fransblhogervorst commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT mattiarookus commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT jmargrietcollee commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT nicolinehoogerbrugge commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT keesepvanroozendaal commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT hebonstudycollaborators commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT marionpiedmonte commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT wendyrubinstein commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT stacynerenstone commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT lindavanle commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT stephanievblank commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT trinidadcaldes commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT migueldelahoya commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT helinevanlinna commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT kristiinaaittomaki commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT conxilazaro commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT ignacioblanco commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT adalgeirarason commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT oskartjohannsson commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT rosabbarkardottir commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT peterdevilee commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT olofunmilayoiolopade commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT susanlneuhausen commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT xianshuwang commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT zacharysfredericksen commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT paolopeterlongo commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT siranoushmanoukian commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT monicabarile commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT alessandraviel commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT paoloradice commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT catherinemphelan commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT stevennarod commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT gadrennert commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT flaviolejbkowicz commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT anathflugelman commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT irenelandrulis commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT gordglendon commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT hilmiozcelik commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT ocgn commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT amandaetoland commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT marcomontagna commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT emmadandrea commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT eitanfriedman commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT yaellaitman commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT akeborg commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT marybeattie commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT susanjramus commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT susanmdomchek commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT katherinelnathanson commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT timrebbeck commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT amandabspurdle commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT xiaoqingchen commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT heleneholland commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT kconfab commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT esthermjohn commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT johnlhopper commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT saundrasbuys commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT marybdaly commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT melissacsouthey commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT marybethterry commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT nadinetung commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT thomasvovereemhansen commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT finncnielsen commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT markhgreene commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT phuonglmai commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT anaosorio commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT mercedesduran commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT raquelandres commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT javierbenitez commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT jeffreynweitzel commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT judygarber commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT utehamann commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT embrace commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT susanpeock commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT margaretcook commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT clareoliver commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT debrafrost commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT radkaplatte commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT dgarethevans commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT fionalalloo commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT roseeles commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT louiseizatt commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT lisawalker commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT jacquelineeason commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT julianbarwell commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT andrewkgodwin commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT ritakschmutzler commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT barbarawappenschmidt commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT stefanieengert commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT norbertarnold commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT dorotheagadzicki commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT michaeldean commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT bertgold commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT robertjklein commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT fergusjcouch commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT georgiachenevixtrench commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT douglasfeaston commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT markjdaly commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT antoniscantoniou commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT davidmaltshuler commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer AT kennethoffit commongeneticvariantsandmodificationofpenetranceofbrca2associatedbreastcancer |
_version_ |
1718424506101399552 |
spelling |
oai:doaj.org-article:c7a705a431ab474c952a747fa473b1e82021-11-18T06:17:56ZCommon genetic variants and modification of penetrance of BRCA2-associated breast cancer.1553-73901553-740410.1371/journal.pgen.1001183https://doaj.org/article/c7a705a431ab474c952a747fa473b1e82010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21060860/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.Mia M GaudetTomas KirchhoffTodd GreenJoseph VijaiJoshua M KornCandace GuiducciAyellet V SegrèKate McGeeLesley McGuffogChristiana KartsonakiJonathan MorrisonSue HealeyOlga M SinilnikovaDominique Stoppa-LyonnetSylvie MazoyerMarion Gauthier-VillarsHagay SobolMichel LongyMarc FrenayGEMO Study CollaboratorsFrans B L HogervorstMatti A RookusJ Margriet ColléeNicoline HoogerbruggeKees E P van RoozendaalHEBON Study CollaboratorsMarion PiedmonteWendy RubinsteinStacy NerenstoneLinda Van LeStephanie V BlankTrinidad CaldésMiguel de la HoyaHeli NevanlinnaKristiina AittomäkiConxi LazaroIgnacio BlancoAdalgeir ArasonOskar T JohannssonRosa B BarkardottirPeter DevileeOlofunmilayo I OlopadeSusan L NeuhausenXianshu WangZachary S FredericksenPaolo PeterlongoSiranoush ManoukianMonica BarileAlessandra VielPaolo RadiceCatherine M PhelanSteven NarodGad RennertFlavio LejbkowiczAnath FlugelmanIrene L AndrulisGord GlendonHilmi OzcelikOCGNAmanda E TolandMarco MontagnaEmma D'AndreaEitan FriedmanYael LaitmanAke BorgMary BeattieSusan J RamusSusan M DomchekKatherine L NathansonTim RebbeckAmanda B SpurdleXiaoqing ChenHelene HollandkConFabEsther M JohnJohn L HopperSaundra S BuysMary B DalyMelissa C SoutheyMary Beth TerryNadine TungThomas V Overeem HansenFinn C NielsenMark H GreenePhuong L MaiAna OsorioMercedes DuránRaquel AndresJavier BenítezJeffrey N WeitzelJudy GarberUte HamannEMBRACESusan PeockMargaret CookClare OliverDebra FrostRadka PlatteD Gareth EvansFiona LallooRos EelesLouise IzattLisa WalkerJacqueline EasonJulian BarwellAndrew K GodwinRita K SchmutzlerBarbara WappenschmidtStefanie EngertNorbert ArnoldDorothea GadzickiMichael DeanBert GoldRobert J KleinFergus J CouchGeorgia Chenevix-TrenchDouglas F EastonMark J DalyAntonis C AntoniouDavid M AltshulerKenneth OffitPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 6, Iss 10, p e1001183 (2010) |