Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

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Common genetic variants and modification of penetrance of BRCA2-associated breast cancer


نویسنده	gaudet m.m. ,kirchhoff t. ,green t. ,vijai j. ,korn j.m. ,guiducci c. ,segrè a.v. ,mcgee k. ,mcguffog l. ,kartsonaki c. ,morrison j. ,healey s. ,sinilnikova o.m. ,stoppa-lyonnet d. ,mazoyer s. ,gauthier-villars m. ,sobol h. ,longy m. ,frenay m. ,hogervorst f.b.l. ,rookus m.a. ,collée j.m. ,hoogerbrugge n. ,van roozendaal k.e.p. ,piedmonte m. ,rubinstein w. ,nerenstone s. ,van le l. ,blank s.v. ,caldés t. ,de la hoya m. ,nevanlinna h. ,aittomäki k. ,lazaro c. ,blanco i. ,arason a. ,johannsson o.t. ,barkardottir r.b. ,devilee p. ,olopade o.i. ,neuhausen s.l. ,wang x. ,fredericksen z.s. ,peterlongo p. ,manoukian s. ,barile m. ,viel a. ,radice p. ,phelan c.m. ,narod s. ,rennert g. ,lejbkowicz f. ,flugelman a. ,andrulis i.l. ,glendon g. ,ozcelik h. ,toland a.e. ,montagna m. ,d'andrea e. ,friedman e. ,laitman y. ,borg a. ,beattie m. ,ramus s.j. ,domchek s.m. ,nathanson k.l. ,rebbeck t. ,spurdle a.b. ,chen x. ,holland h. ,john e.m. ,hopper j.l. ,buys s.s. ,daly m.b. ,southey m.c. ,terry m.b. ,tung n. ,hansen t.v.o. ,nielsen f.c. ,greene m.i. ,mai p.l. ,osorio a. ,durán m. ,andres r. ,benítez j. ,weitzel j.n. ,garber j. ,hamann u. ,peock s. ,cook m. ,oliver c. ,frost d. ,platte r. ,evans d.g. ,lalloo f. ,eeles r. ,izatt l. ,walker l. ,eason j. ,barwell j. ,godwin a.k. ,schmutzler r.k. ,wappenschmidt b. ,engert s. ,arnold n. ,gadzicki d. ,dean m. ,gold b. ,klein r.j. ,couch f.j. ,chenevix-trench g. ,easton d.f. ,daly m.j. ,antoniou a.c. ,altshuler d.m. ,offit k.
منبع	plos genetics - 2010 - دوره : 6 - شماره : 10 - صفحه:1 -12
چکیده	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 brca26174delt 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,brca26174delt. the combined per allele hr of the minor allele for the novel loci rs16917302 was 0.75 (95% ci 0.66-0.86,p=3:8×10-5) and for rs311499 was 0.72 (95% ci 0.61-0.85,p=6:6-×10-5). fgfr2 rs2981575 had the strongest association with breast cancer risk (per allele hr = 1.28,95% ci 1.18-1.39,p=1:2×10-8). 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.

آدرس	department of epidemiology and population health,department of obstetrics and gynecology and women's health,albert einstein college of medicine,new york,ny, United States, clinical genetics service,department of medicine,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny,united states,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny, United States, broad institute of harvard and massachusetts institute of technology,harvard medical school,boston,ma, United States, clinical genetics service,department of medicine,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny, United States, broad institute of harvard and massachusetts institute of technology,harvard medical school,boston,ma, United States, broad institute of harvard and massachusetts institute of technology,harvard medical school,boston,ma, United States, broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,center for human genetic research,massachusetts general hospital,boston,ma,united states,department of molecular biology,massachusetts general hospital,boston,ma, United States, center for cancer research,cancer inflammation program,human genetics section,national cancer institute - frederick,frederick,md, United States, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, unité mixte de génétique constitutionnelle des cancers fréquents,centre hospitalier universitaire de lyon,centre léon bérard,lyon,france,equipe labellisée ligue 2008,umr5201 cnrs,centre léon bérard,université de lyon,lyon, France, institut curie,service de génétique,inserm u830,f-75248,université paris descartes,paris,france,service de genetique oncologique,institut curie,paris, France, equipe labellisée ligue 2008,umr5201 cnrs,centre léon bérard,université de lyon,lyon, France, service de genetique oncologique,institut curie,paris, France, département oncologie génétique,prévention et dépistage,inserm cic-p9502,institut paoli-calmettes/université d'aix-marseille ii,marseille, France, institut bergonié,bordeaux, France, centre antoine lacassagne,nice, France, family cancer clinic,netherlands cancer institute,amsterdam, Netherlands, department of epidemiology,netherlands cancer institute,amsterdam, Netherlands, department of medical oncology,rotterdam family cancer clinic,erasmus university medical center,rotterdam, Netherlands, department of human genetics,radboud university nijmegen medical centre,nijmegen, Netherlands, department of clinical genetics,university medical center,maastricht, Netherlands, gynecologic oncology group statistical and data center,roswell park cancer institute,buffalo,ny, United States, north shore university health system,evanston,il, United States, central connecticut cancer consortium,hartford hospital,hartford,ct, United States, university of north carolina,chapel hill,nc, United States, new york university school of medicine,new york,ny, United States, molecular oncology laboratory,hospital clinico san carlos,madrid, Spain, molecular oncology laboratory,hospital clinico san carlos,madrid, Spain, department of obstetrics and gynecology,helsinki university central hospital,helsinki, Finland, department of clinical genetics,helsinki university central hospital,helsinki, Finland, hereditary cancer program,catalan institute of oncology,barcelona, Spain, hereditary cancer program,catalan institute of oncology,barcelona, Spain, department of oncology,landspitali-lsh,reykjavik,iceland,department of pathology,landspitali-lsh,reykjavik,iceland,faculty of medicine,university of iceland,reykjavik, Iceland, department of oncology,landspitali-lsh,reykjavik,iceland,faculty of medicine,university of iceland,reykjavik, Iceland, department of oncology,landspitali-lsh,reykjavik,iceland,department of pathology,landspitali-lsh,reykjavik,iceland,faculty of medicine,university of iceland,reykjavik, Iceland, department of human genetics and department of pathology,leiden university medical center,leiden, Netherlands, center for clinical cancer genetics and global health,department of medicine,university of chicago medical center,chicago,il, United States, department of population sciences,beckman research institute of the city of hope,duarte,ca, United States, department of laboratory medicine and pathology,mayo clinic,rochester,mn, United States, department of health sciences research,mayo clinic,rochester,mn, United States, unit of genetic susceptibility to cancer,department of experimental oncology and molecular medicine,fondazione irccs istituto nazionale tumori (int),milan,italy,ifom,fondazione istituto firc di oncologia molecolare,milan, Italy, unit of medical genetics,department of preventive and predictive medicine,fondazione irccs istituto nazionale dei tumori (int),milan, Italy, division of cancer prevention and genetics,istituto europeo di oncologia (ieo),milan, Italy, division of experimental oncology 1,centro di riferimento oncologico (cro),irccs,aviano (pn), Italy, ifom,fondazione istituto firc di oncologia molecolare,milan, Italy, moffitt cancer center,tampa,fl, United States, qomen's college research institute,toronto, Canada, chs national cancer control center,department of community medicine and epidemiology,carmel medical center,haifa, Israel, chs national cancer control center,department of community medicine and epidemiology,carmel medical center,haifa, Israel, chs national cancer control center,department of community medicine and epidemiology,carmel medical center,haifa, Israel, samuel lunenfeld research institute,mount sinai hospital,toronto,canada,cancer care ontario,ontario cancer genetics network,university of toronto,toronto, Canada, cancer care ontario,ontario cancer genetics network,university of toronto,toronto, Canada, samuel lunenfeld research institute,mount sinai hospital,toronto,canada,cancer care ontario,ontario cancer genetics network,university of toronto,toronto, Canada, departments of molecular virology,immunology,and medical genetics and internal medicine,ohio state university,columbus,oh, United States, immunology and molecular oncology unit,istituto oncologico veneto,irccs,padua, Italy, immunology and molecular oncology unit,istituto oncologico veneto,irccs,padua,italy,department of oncology and surgical sciences,university of padua,padua, Italy, the susan levy gertner oncogenetics unit,institute of genetics,sheba medical center,tel hashomer, Israel, the susan levy gertner oncogenetics unit,institute of genetics,sheba medical center,tel hashomer, Israel, department of oncology,lund university,lund, Sweden, division of general internal medicine,department of medicine,university of california san francisco,san francisco,ca, United States, gynaecological oncology unit,ucl ega institute for women's health,university college london, United Kingdom, department of oncology,the hospital of the university of pennsylvania,philadelphia,pa, United States, department of cell and molecular biology,university of pennsylvania school of medicine,philadelphia,pa, United States, center for clinical epidemiology and biostatistics,department of biostatistics and epidemiology,the university of pennsylvania school of medicine,philadelphia,pa, United States, genetics and population health division,queensland institute of medical research,brisbane, Australia, genetics and population health division,queensland institute of medical research,brisbane, Australia, genetics and population health division,queensland institute of medical research,brisbane, Australia, cancer prevention institute of california,fremont,ca, United States, centre for genetic epidemiology,university of melbourne,melbourne, Australia, huntsman cancer institute,university of utah,salt lake city,ut, United States, fox chase cancer center,philadelphia,pa, United States, centre for genetic epidemiology,university of melbourne,melbourne, Australia, department of epidemiology,mailman school of public health,columbia university,new york,ny, United States, division of hematology-oncology,beth israel deaconess medical center,boston,ma, United States, department of clinical biochemistry,rigshospitalet,copenhagen university hospitalet,copenhagen, Denmark, department of clinical biochemistry,rigshospitalet,copenhagen university hospitalet,copenhagen, Denmark, clinical genetics branch,national cancer institute,rockville,md, United States, clinical genetics branch,national cancer institute,rockville,md, United States, human genetics group,human cancer genetics programme,spanish national cancer research centre,madrid, Spain, institute of biology and molecular genetics,universidad de valladolid (ibgm-uva),valladolid, Spain, oncology service,hospital clínico universitario lozano blesa,zaragoza, Spain, human genetics group and genotyping unit,human cancer genetics programme,spanish national cancer research centre,madrid, Spain, city of hope cancer center,duarte,ca, United States, dana farber cancer institute,harvard university,boston,ma, United States, molecular genetics of breast cancer,deutsches krebsforschungszentrum (dkfz),heidelberg, Germany, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, genetic medicine,manchester academic health sciences centre,central manchester university hospitals nhs foundation trust,manchester, United Kingdom, genetic medicine,manchester academic health sciences centre,central manchester university hospitals nhs foundation trust,manchester, United Kingdom, oncogenetics team,the institute of cancer research and royal marsden nhs foundation trust,london, United Kingdom, clinical genetics,guy's and st. thomas' nhs foundation trust,london, United Kingdom, oxford regional genetics service,churchill hospital,oxford, United Kingdom, nottingham clinical genetics service,nottingham university hospitals nhs trust,nottingham, United Kingdom, leicestershire clinical genetics service,university hospitals of leicester nhs trust,leicester, United Kingdom, women's cancer program,department of medical oncology,fox chase cancer center,philadelphia,pa, United States, centre of familial breast and ovarian cancer,department of gynaecology and obstetrics,centre for integrated oncology (cio),university hospital of cologne,cologne, Germany, centre of familial breast and ovarian cancer,department of gynaecology and obstetrics,centre for integrated oncology (cio),university hospital of cologne,cologne, Germany, department of gynaecology and obstetrics,division of tumor genetics,klinikum rechts der isar,technical university munich,munich, Germany, department of gynaecology and obstetrics,university hospital of schleswig-holstein,christian-albrechts university kiel,kiel, Germany, institute of cell and molecular pathology,hannover medical school,hannover, Germany, center for cancer research,cancer inflammation program,human genetics section,national cancer institute - frederick,frederick,md, United States, center for cancer research,cancer inflammation program,human genetics section,national cancer institute - frederick,frederick,md, United States, program in cancer biology and genetics,memorial sloan-kettering cancer center,new york,ny, United States, department of laboratory medicine and pathology,mayo clinic,rochester,mn, United States, peter maccallum cancer centre,melbourne, Australia, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, broad institute of harvard and massachusetts institute of technology,harvard medical school,boston,ma, United States, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,cambridge, United Kingdom, broad institute of harvard and massachusetts institute of technology,harvard medical school,boston,ma, United States, clinical genetics service,department of medicine,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny, United States



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