Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer (vol 313, pg 1347, 2015)

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dc.contributor.author Rebbeck, Timothy R.
dc.contributor.author Mitra, Nandita
dc.contributor.author Wan, Fei
dc.contributor.author Sinilnikova, Olga M.
dc.contributor.author Healey, Sue
dc.contributor.author McGuffog, Lesley
dc.contributor.author Mazoyer, Sylvie
dc.contributor.author Chenevix-Trench, Georgia
dc.contributor.author Easton, Douglas F.
dc.contributor.author Antoniou, Antonis C.
dc.contributor.author Nathanson, Katherine L.
dc.contributor.author CIMBA Consortium
dc.contributor.author Nevanlinna, Heli
dc.contributor.author Aittomäki, Kristiina
dc.date.accessioned 2017-10-18T08:06:01Z
dc.date.available 2017-10-18T08:06:01Z
dc.date.issued 2015-04-07
dc.identifier.citation Rebbeck , T R , Mitra , N , Wan , F , Sinilnikova , O M , Healey , S , McGuffog , L , Mazoyer , S , Chenevix-Trench , G , Easton , D F , Antoniou , A C , Nathanson , K L , CIMBA Consortium , Nevanlinna , H & Aittomäki , K 2015 , ' Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer (vol 313, pg 1347, 2015) ' , JAMA : The Journal of the American Medical Association , vol. 314 , no. 6 , pp. 628 . https://doi.org/10.1001/jama.2014.5985
dc.identifier.other PURE: 59708201
dc.identifier.other PURE UUID: 72759d7b-f5bd-4ad9-ba19-a0640284775a
dc.identifier.other WOS: 000359388600030
dc.identifier.uri http://hdl.handle.net/10138/225912
dc.description Heli Nevanlinna ja Kristiina Aittomäki ovat CIMBA Consortium -työryhmän jäseniä.
dc.description.abstract IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317(12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682(6%) with ovarian cancer, 272(2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% Cl, 1.22-1.74; P = 2 x 10(-6)), c.4328 to c.4945 (BCCR2; RH R = 1.34; 95% Cl, 1.01-1.78; P =.04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% Cl, 1.22-1.55; P = 6 x 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% Cl, 0.56-0.70; P = 9 x 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% Cl, 1.06-2.78; P =.03), c.772 to c.1806 (BCCRI; RHR = 1.63; 95% Cl, 1.10-2.40; P =.01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% Cl, 1.69-3.16; P =.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% Cl, 0.44-0.60; P = 6 x 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% Cl, 0.41-0.80; P =.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations. en
dc.format.extent 1
dc.language.iso eng
dc.relation.ispartof JAMA : The Journal of the American Medical Association
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject MESSENGER-RNA DECAY
dc.subject UNKNOWN CLINICAL-SIGNIFICANCE
dc.subject DNA-SEQUENCE VARIANTS
dc.subject SUSCEPTIBILITY GENE
dc.subject GERMLINE MUTATIONS
dc.subject MOUSE MODELS
dc.subject CARRIERS
dc.subject PROTEINS
dc.subject POSITION
dc.subject REGION
dc.subject 3123 Gynaecology and paediatrics
dc.subject 3122 Cancers
dc.subject 3111 Biomedicine
dc.title Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer (vol 313, pg 1347, 2015) en
dc.type Article
dc.contributor.organization Department of Obstetrics and Gynecology
dc.contributor.organization Clinicum
dc.contributor.organization Medicum
dc.contributor.organization Kristiina Aittomäki / Principal Investigator
dc.contributor.organization Department of Medical and Clinical Genetics
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1001/jama.2014.5985
dc.relation.issn 0098-7484
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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