Association of Type and Location ofBRCA1andBRCA2Mutations With Risk of Breast and Ovarian Cancer

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 × 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 (BCCR23, RHR = 1.38; 95% CI, 1.22–1.55; P = 6 × 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 × 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 (BCCR13; 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 × 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.

Ovarian cancer

“…Both the location of the BRCA mutation within the gene and the type of the mutation might also influence risk of developing ovarian cancer; the risk of developing breast cancer or ovarian cancer, as well as the median age at diagnosis, can vary according to mutation type, nucleotide position and the functional consequence of the mutation in patients with germline BRCA1 or BRCA2 mutations (21).…”

Az örökletes emlőrák szűrésének, megelőzésének és kezelésének új nemzetközi irányvonalai – hazai vonatkozásokkal

“…A munkacsoport úttörő szerepet játszott az örökletes emlőrákban kulcsfontosságú, BRCA1 gén működésének kimutatásában, többek között a gént érintő alternatív splicing szerepének és szabályozásának bemutatásában, illetve azok szövetspecifikus variánsainak leírásában [11,12]. A Breast Cancer Linkage Consortium (BCLC) nevű európai kutatói hálózathoz társulva mutatták ki, hogy a BRCA1 tumorszuppresszor gén, megjelölve a gén pontos kromoszomális helyét a BRCA1-régión belül, és kimutatva, hogy a családi halmozódású betegeknél az úgy-nevezett vad allél elvész, emiatt a mutáns allél hatása érvényesül [13]. Az emlőrák kialakulásáért felelős továb-bi genetikai variánsokat írtak le a genom több szakaszá-nak vizsgálata során meghatározva azok kromoszomális helyét is [14].…”

Quantitative detection of methylation of FHIT and BRCA1 promoters in the serum of ductal breast cancer patients

“…According to the data, the development of carcinoma is a complicated process that involves gene mutation and epigenetic changes. For example, individuals possessing the breast cancer susceptibility gene 1 (BRCA1) mutation have a higher risk of breast and ovarian cancers [1]. Some data shows epigenetic alterations may result in the silencing of the tumor suppressor gene [2].…”