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    Breast cancer research : BCR. doi: 10.1186/s13058-016-0768-3. pii: 10.1186/s13058-016-0768-3
    Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women.
    Rebbeck TR1,  Friebel TM2,  Mitra N3,  Wan F4,  Chen S5,  Andrulis IL6,  Apostolou P7,  Arnold N8,  Arun BK9,  Barrowdale D10,  Benitez J11,  Berger R12,  Berthet P13,  Borg A14,  Buys SS15,  Caldes T16,  Carter J17,  Chiquette J18,  Claes KB19,  Couch FJ20,  Cybulski C21,  Daly MB22,  de la Hoya M23,  Diez O24,  Domchek SM25,  Nathanson KL26,  Durda K27,  Ellis S28,  Evans DG29,  Foretova L30,  Friedman E31,  Frost D32,  Ganz PA33,  Garber J34,  Glendon G35,  Godwin AK36,  Greene MH37,  Gronwald J38,  Hahnen E39,  Hallberg E40,  Hamann U41,  Hansen TV42,  Imyanitov EN43,  Isaacs C44,  Jakubowska A45,  Janavicius R46,  Jaworska-Bieniek K47,  John EM48,  Karlan BY49,  Kaufman B50,  Investigators K51,  Kwong A52,  Laitman Y53,  Lasset C54,  Lazaro C55,  Lester J56,  Loman N57,  Lubinski J58,  Manoukian S59,  Mitchell G60,  Montagna M61,  Neuhausen SL62,  Nevanlinna H63,  Niederacher D64,  Nussbaum RL65,  Offit K66,  Olah E67,  Olopade OI68,  Park SK69,  Piedmonte M70,  Radice P71,  Rappaport-Fuerhauser C72,  Rookus MA73,  Seynaeve C74,  Simard J75,  Singer CF76,  Soucy P77,  Southey M78,  Stoppa-Lyonnet D79,  Sukiennicki G80,  Szabo CI81,  Tancredi M82,  Teixeira MR83,  Teo SH84,  Terry MB85,  Thomassen M86,  Tihomirova L87,  Tischkowitz M88,  Toland AE89,  Toloczko-Grabarek A90,  Tung N91,  van Rensburg EJ92,  Villano D93,  Wang-Gohrke S94,  Wappenschmidt B95,  Weitzel JN96,  Zidan J97,  Zorn KK98,  McGuffog L99,  Easton D100,  Chenevix-Trench G101,  Antoniou AC102,  Ramus SJ103
    Author information
    Abstract

    BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.

    METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.

    RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.

    CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.


    KEYWORDS: BRCA1, BRCA2, Hereditary breast and ovarian cancer, Transheterozygosity

    Publikations ID: 27836010
    Quelle: öffnen
     
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