Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

2.50
Hdl Handle:
http://hdl.handle.net/11287/593899
Title:
Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer
Authors:
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; Laitman, Y.; Kushnir, A.; Paluch-Shimon, S.; Berger, R.; Zidan, J.; Friedman, E.; Ehrencrona, H.; Stenmark-Askmalm, M.; Einbeigi, Z.; Loman, N.; Harbst, K.; Rantala, J.; Melin, B.; Huo, D.; Olopade, O. I.; Seldon, J.; Ganz, P. A.; Nussbaum, R. L.; Chan, S. B.; Odunsi, K.; Gayther, S. A.; Domchek, S. M.; Arun, B. K.; Lu, K. H.; Mitchell, G.; Karlan, B. Y.; Walsh, C.; Lester, J.; Godwin, A. K.; Pathak, H.; Ross, E.; Daly, Mark B.; Whittemore, A. S.; John, E. M.; Miron, A.; Terry, M. B.; Chung, W. K.; Goldgar, D. E.; Buys, S. S.; Janavicius, R.; Tihomirova, L.; Tung, N.; Dorfling, C. M.; van Rensburg, E. J.; Steele, L.; Neuhausen, S. L.; Ding, Y. C.; Ejlertsen, B.; Gerdes, A. M.; Hansen, Tv; Ramon y Cajal, T.; Osorio, A.; Benitez, J.; Godino, J.; Tejada, M. I.; Duran, M.; Weitzel, J. N.; Bobolis, K. A.; Sand, S. R.; Fontaine, A.; Savarese, A.; Pasini, B.; Peissel, B.; Bonanni, B.; Zaffaroni, D.; Vignolo-Lutati, F.; Scuvera, G.; Giannini, G.; Bernard, L.; Genuardi, M.; Radice, P.; Dolcetti, R.; Manoukian, S.; Pensotti, V.; Gismondi, V.; Yannoukakos, D.; Fostira, F.; Garber, J.; Torres, D.; Rashid, M. U.; Hamann, U.; Peock, S.; Frost, D.; Platte, R.; Evans, D. G.; Eeles, R.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Brewer, Carole; Hodgson, S.; Morrison, P. J.; Walker, L.; Porteous, M. E.; Kennedy, M. J.; Izatt, L.; Adlard, J.; Donaldson, A.; Ellis, S.; Sharma, P.; Schmutzler, R. K.; Wappenschmidt, B.; Becker, A.; Rhiem, K.; Hahnen, E.; Engel, C.; Meindl, A.; Engert, S.; Ditsch, N.; Arnold, N.; Plendl, H. J.; Mundhenke, C.; Niederacher, D.; Fleisch, M.; Sutter, C.; Bartram, C. R.; Dikow, N.; Wang-Gohrke, S.; Gadzicki, D.; Steinemann, D.; Kast, K.; Beer, M.; Varon-Mateeva, R.; Gehrig, A.; Weber, B. H.; Stoppa-Lyonnet, D.; Sinilnikova, O. M.; Mazoyer, S.; Houdayer, C.; Belotti, M.; Gauthier-Villars, M.; Damiola, F.; Boutry-Kryza, N.; Lasset, C.; Sobol, H.; Peyrat, J. P.; Muller, D.; Fricker, J. P.; Collonge-Rame, M. A.; Mortemousque, I.; Nogues, C.; Rouleau, E.; Isaacs, C.; De Paepe, A.; Poppe, B.; Claes, K.; De Leeneer, K.; Piedmonte, M.; Rodriguez, G.; Wakely, K.; Boggess, J.; Blank, S. V.; Basil, J.; Azodi, M.; Phillips, K. A.; Caldes, T.; de la Hoya, M.; Romero, A.; Nevanlinna, H.; Aittomaki, K.; van der Hout, A. H.; Hogervorst, F. B.; Verhoef, S.; Collee, J. M.; Seynaeve, C.; Oosterwijk, J. C.; Gille, J. J.; Wijnen, J. T.; Gomez Garcia, E. B.; Kets, C. M.; Ausems, M. G.; Aalfs, C. M.; Devilee, P.; Mensenkamp, A. R.; Kwong, A.; Olah, E.; Papp, J.; Diez, O.; Lazaro, C.; Darder, E.; Blanco, I.; Salinas, M.; Jakubowska, A.; Lubinski, J.; Gronwald, J.; Jaworska-Bieniek, K.; Durda, K.; Sukiennicki, G.; Huzarski, T.; Byrski, T.; Cybulski, C.; Toloczko-Grabarek, A.; Zlowocka-Perlowska, E.; Menkiszak, J.; Arason, A.; Barkardottir, R. B.; Simard, J.; Laframboise, R.; Montagna, M.; Agata, S.; Alducci, E.; Peixoto, A.; Teixeira, M. R.; Spurdle, A. B.; Lee, M. H.; Park, S. K.; Kim, S. W.; Friebel, T. M.; Couch, F. J.; Lindor, N. M.; Pankratz, V. S.; Guidugli, L.; Wang, X.; Tischkowitz, M.; Foretova, L.; Vijai, J.; Offit, K.; Robson, M.; Rau-Murthy, R.; Kauff, N.; Fink-Retter, A.; Singer, C. F.; Rappaport, C.; Gschwantler-Kaulich, D.; Pfeiler, G.; Tea, M. K.; Berger, A.; Greene, M. H.; Mai, P. L.; Imyanitov, E. N.; Toland, A. E.; Senter, L.; Bojesen, A.; Pedersen, I. S.; Skytte, A. B.; Sunde, L.; Thomassen, M.; Moeller, S. T.; Kruse, T. A.; Jensen, U. B.; Caligo, M. A.; Aretini, P.; Teo, S. H.; Selkirk, C. G.; Hulick, P. J.; Andrulis, I.
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% CI, 1.22-1.74; P = 2 x 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 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% CI, 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% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 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% CI, 0.44-0.60; P = 6 x 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 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.
Citation:
JAMA. 2015 Apr 7;313(13):1347-61.
Publisher:
JAMA
Journal:
JAMA
Issue Date:
7-Apr-2015
URI:
http://hdl.handle.net/11287/593899
DOI:
10.1001/jama.2014.5985
PubMed ID:
25849179
Additional Links:
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.5985
Type:
Observational Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1538-3598
Appears in Collections:
2015 RD&E publications; Clinical Genetics (Peninsula Genetics)

Full metadata record

DC FieldValue Language
dc.contributor.authorRebbeck, T. R.en
dc.contributor.authorMitra, N.en
dc.contributor.authorWan, F.en
dc.contributor.authorSinilnikova, O. M.en
dc.contributor.authorHealey, S.en
dc.contributor.authorMcGuffog, L.en
dc.contributor.authorMazoyer, S.en
dc.contributor.authorChenevix-Trench, G.en
dc.contributor.authorEaston, D. F.en
dc.contributor.authorAntoniou, A. C.en
dc.contributor.authorNathanson, K. L.en
dc.contributor.authorCimba Consortiumen
dc.contributor.authorLaitman, Y.en
dc.contributor.authorKushnir, A.en
dc.contributor.authorPaluch-Shimon, S.en
dc.contributor.authorBerger, R.en
dc.contributor.authorZidan, J.en
dc.contributor.authorFriedman, E.en
dc.contributor.authorEhrencrona, H.en
dc.contributor.authorStenmark-Askmalm, M.en
dc.contributor.authorEinbeigi, Z.en
dc.contributor.authorLoman, N.en
dc.contributor.authorHarbst, K.en
dc.contributor.authorRantala, J.en
dc.contributor.authorMelin, B.en
dc.contributor.authorHuo, D.en
dc.contributor.authorOlopade, O. I.en
dc.contributor.authorSeldon, J.en
dc.contributor.authorGanz, P. A.en
dc.contributor.authorNussbaum, R. L.en
dc.contributor.authorChan, S. B.en
dc.contributor.authorOdunsi, K.en
dc.contributor.authorGayther, S. A.en
dc.contributor.authorDomchek, S. M.en
dc.contributor.authorArun, B. K.en
dc.contributor.authorLu, K. H.en
dc.contributor.authorMitchell, G.en
dc.contributor.authorKarlan, B. Y.en
dc.contributor.authorWalsh, C.en
dc.contributor.authorLester, J.en
dc.contributor.authorGodwin, A. K.en
dc.contributor.authorPathak, H.en
dc.contributor.authorRoss, E.en
dc.contributor.authorDaly, Mark B.en
dc.contributor.authorWhittemore, A. S.en
dc.contributor.authorJohn, E. M.en
dc.contributor.authorMiron, A.en
dc.contributor.authorTerry, M. B.en
dc.contributor.authorChung, W. K.en
dc.contributor.authorGoldgar, D. E.en
dc.contributor.authorBuys, S. S.en
dc.contributor.authorJanavicius, R.en
dc.contributor.authorTihomirova, L.en
dc.contributor.authorTung, N.en
dc.contributor.authorDorfling, C. M.en
dc.contributor.authorvan Rensburg, E. J.en
dc.contributor.authorSteele, L.en
dc.contributor.authorNeuhausen, S. L.en
dc.contributor.authorDing, Y. C.en
dc.contributor.authorEjlertsen, B.en
dc.contributor.authorGerdes, A. M.en
dc.contributor.authorHansen, Tven
dc.contributor.authorRamon y Cajal, T.en
dc.contributor.authorOsorio, A.en
dc.contributor.authorBenitez, J.en
dc.contributor.authorGodino, J.en
dc.contributor.authorTejada, M. I.en
dc.contributor.authorDuran, M.en
dc.contributor.authorWeitzel, J. N.en
dc.contributor.authorBobolis, K. A.en
dc.contributor.authorSand, S. R.en
dc.contributor.authorFontaine, A.en
dc.contributor.authorSavarese, A.en
dc.contributor.authorPasini, B.en
dc.contributor.authorPeissel, B.en
dc.contributor.authorBonanni, B.en
dc.contributor.authorZaffaroni, D.en
dc.contributor.authorVignolo-Lutati, F.en
dc.contributor.authorScuvera, G.en
dc.contributor.authorGiannini, G.en
dc.contributor.authorBernard, L.en
dc.contributor.authorGenuardi, M.en
dc.contributor.authorRadice, P.en
dc.contributor.authorDolcetti, R.en
dc.contributor.authorManoukian, S.en
dc.contributor.authorPensotti, V.en
dc.contributor.authorGismondi, V.en
dc.contributor.authorYannoukakos, D.en
dc.contributor.authorFostira, F.en
dc.contributor.authorGarber, J.en
dc.contributor.authorTorres, D.en
dc.contributor.authorRashid, M. U.en
dc.contributor.authorHamann, U.en
dc.contributor.authorPeock, S.en
dc.contributor.authorFrost, D.en
dc.contributor.authorPlatte, R.en
dc.contributor.authorEvans, D. G.en
dc.contributor.authorEeles, R.en
dc.contributor.authorDavidson, R.en
dc.contributor.authorEccles, D.en
dc.contributor.authorCole, T.en
dc.contributor.authorCook, J.en
dc.contributor.authorBrewer, Caroleen
dc.contributor.authorHodgson, S.en
dc.contributor.authorMorrison, P. J.en
dc.contributor.authorWalker, L.en
dc.contributor.authorPorteous, M. E.en
dc.contributor.authorKennedy, M. J.en
dc.contributor.authorIzatt, L.en
dc.contributor.authorAdlard, J.en
dc.contributor.authorDonaldson, A.en
dc.contributor.authorEllis, S.en
dc.contributor.authorSharma, P.en
dc.contributor.authorSchmutzler, R. K.en
dc.contributor.authorWappenschmidt, B.en
dc.contributor.authorBecker, A.en
dc.contributor.authorRhiem, K.en
dc.contributor.authorHahnen, E.en
dc.contributor.authorEngel, C.en
dc.contributor.authorMeindl, A.en
dc.contributor.authorEngert, S.en
dc.contributor.authorDitsch, N.en
dc.contributor.authorArnold, N.en
dc.contributor.authorPlendl, H. J.en
dc.contributor.authorMundhenke, C.en
dc.contributor.authorNiederacher, D.en
dc.contributor.authorFleisch, M.en
dc.contributor.authorSutter, C.en
dc.contributor.authorBartram, C. R.en
dc.contributor.authorDikow, N.en
dc.contributor.authorWang-Gohrke, S.en
dc.contributor.authorGadzicki, D.en
dc.contributor.authorSteinemann, D.en
dc.contributor.authorKast, K.en
dc.contributor.authorBeer, M.en
dc.contributor.authorVaron-Mateeva, R.en
dc.contributor.authorGehrig, A.en
dc.contributor.authorWeber, B. H.en
dc.contributor.authorStoppa-Lyonnet, D.en
dc.contributor.authorSinilnikova, O. M.en
dc.contributor.authorMazoyer, S.en
dc.contributor.authorHoudayer, C.en
dc.contributor.authorBelotti, M.en
dc.contributor.authorGauthier-Villars, M.en
dc.contributor.authorDamiola, F.en
dc.contributor.authorBoutry-Kryza, N.en
dc.contributor.authorLasset, C.en
dc.contributor.authorSobol, H.en
dc.contributor.authorPeyrat, J. P.en
dc.contributor.authorMuller, D.en
dc.contributor.authorFricker, J. P.en
dc.contributor.authorCollonge-Rame, M. A.en
dc.contributor.authorMortemousque, I.en
dc.contributor.authorNogues, C.en
dc.contributor.authorRouleau, E.en
dc.contributor.authorIsaacs, C.en
dc.contributor.authorDe Paepe, A.en
dc.contributor.authorPoppe, B.en
dc.contributor.authorClaes, K.en
dc.contributor.authorDe Leeneer, K.en
dc.contributor.authorPiedmonte, M.en
dc.contributor.authorRodriguez, G.en
dc.contributor.authorWakely, K.en
dc.contributor.authorBoggess, J.en
dc.contributor.authorBlank, S. V.en
dc.contributor.authorBasil, J.en
dc.contributor.authorAzodi, M.en
dc.contributor.authorPhillips, K. A.en
dc.contributor.authorCaldes, T.en
dc.contributor.authorde la Hoya, M.en
dc.contributor.authorRomero, A.en
dc.contributor.authorNevanlinna, H.en
dc.contributor.authorAittomaki, K.en
dc.contributor.authorvan der Hout, A. H.en
dc.contributor.authorHogervorst, F. B.en
dc.contributor.authorVerhoef, S.en
dc.contributor.authorCollee, J. M.en
dc.contributor.authorSeynaeve, C.en
dc.contributor.authorOosterwijk, J. C.en
dc.contributor.authorGille, J. J.en
dc.contributor.authorWijnen, J. T.en
dc.contributor.authorGomez Garcia, E. B.en
dc.contributor.authorKets, C. M.en
dc.contributor.authorAusems, M. G.en
dc.contributor.authorAalfs, C. M.en
dc.contributor.authorDevilee, P.en
dc.contributor.authorMensenkamp, A. R.en
dc.contributor.authorKwong, A.en
dc.contributor.authorOlah, E.en
dc.contributor.authorPapp, J.en
dc.contributor.authorDiez, O.en
dc.contributor.authorLazaro, C.en
dc.contributor.authorDarder, E.en
dc.contributor.authorBlanco, I.en
dc.contributor.authorSalinas, M.en
dc.contributor.authorJakubowska, A.en
dc.contributor.authorLubinski, J.en
dc.contributor.authorGronwald, J.en
dc.contributor.authorJaworska-Bieniek, K.en
dc.contributor.authorDurda, K.en
dc.contributor.authorSukiennicki, G.en
dc.contributor.authorHuzarski, T.en
dc.contributor.authorByrski, T.en
dc.contributor.authorCybulski, C.en
dc.contributor.authorToloczko-Grabarek, A.en
dc.contributor.authorZlowocka-Perlowska, E.en
dc.contributor.authorMenkiszak, J.en
dc.contributor.authorArason, A.en
dc.contributor.authorBarkardottir, R. B.en
dc.contributor.authorSimard, J.en
dc.contributor.authorLaframboise, R.en
dc.contributor.authorMontagna, M.en
dc.contributor.authorAgata, S.en
dc.contributor.authorAlducci, E.en
dc.contributor.authorPeixoto, A.en
dc.contributor.authorTeixeira, M. R.en
dc.contributor.authorSpurdle, A. B.en
dc.contributor.authorLee, M. H.en
dc.contributor.authorPark, S. K.en
dc.contributor.authorKim, S. W.en
dc.contributor.authorFriebel, T. M.en
dc.contributor.authorCouch, F. J.en
dc.contributor.authorLindor, N. M.en
dc.contributor.authorPankratz, V. S.en
dc.contributor.authorGuidugli, L.en
dc.contributor.authorWang, X.en
dc.contributor.authorTischkowitz, M.en
dc.contributor.authorForetova, L.en
dc.contributor.authorVijai, J.en
dc.contributor.authorOffit, K.en
dc.contributor.authorRobson, M.en
dc.contributor.authorRau-Murthy, R.en
dc.contributor.authorKauff, N.en
dc.contributor.authorFink-Retter, A.en
dc.contributor.authorSinger, C. F.en
dc.contributor.authorRappaport, C.en
dc.contributor.authorGschwantler-Kaulich, D.en
dc.contributor.authorPfeiler, G.en
dc.contributor.authorTea, M. K.en
dc.contributor.authorBerger, A.en
dc.contributor.authorGreene, M. H.en
dc.contributor.authorMai, P. L.en
dc.contributor.authorImyanitov, E. N.en
dc.contributor.authorToland, A. E.en
dc.contributor.authorSenter, L.en
dc.contributor.authorBojesen, A.en
dc.contributor.authorPedersen, I. S.en
dc.contributor.authorSkytte, A. B.en
dc.contributor.authorSunde, L.en
dc.contributor.authorThomassen, M.en
dc.contributor.authorMoeller, S. T.en
dc.contributor.authorKruse, T. A.en
dc.contributor.authorJensen, U. B.en
dc.contributor.authorCaligo, M. A.en
dc.contributor.authorAretini, P.en
dc.contributor.authorTeo, S. H.en
dc.contributor.authorSelkirk, C. G.en
dc.contributor.authorHulick, P. J.en
dc.contributor.authorAndrulis, I.en
dc.date.accessioned2016-01-19T12:37:04Zen
dc.date.available2016-01-19T12:37:04Zen
dc.date.issued2015-04-07en
dc.identifier.citationJAMA. 2015 Apr 7;313(13):1347-61.en
dc.identifier.issn1538-3598en
dc.identifier.pmid25849179en
dc.identifier.doi10.1001/jama.2014.5985en
dc.identifier.urihttp://hdl.handle.net/11287/593899en
dc.description.abstractIMPORTANCE: 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% CI, 1.22-1.74; P = 2 x 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 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% CI, 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% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 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% CI, 0.44-0.60; P = 6 x 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 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.language.isoengen
dc.publisherJAMAen
dc.relation.urlhttp://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.5985en
dc.titleAssociation of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian canceren
dc.typeObservational Studyen
dc.typeResearch Support, N.I.H., Extramuralen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalJAMAen

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