Division of Gynecology and Oncology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel.
The Centre for Research in Women's Health, Toronto, Ontario, Canada.
Ann Oncol. 2011 Apr;22(4):964-966. doi: 10.1093/annonc/mdq460. Epub 2010 Oct 5.
The frequency and characteristics of disease in individuals who concomitantly harbor pathogenic mutations in both BRCA1 and BRCA2 genes are not established.
Data were collected from the database of Clalit Health Services National Familial Cancer Consultation Service. Probands referred to this clinical service and their family members are routinely tested for the three Jewish founder mutations (BRCA1: 185delAG, 5382insC, BRCA2: 6174delT). In addition, carriers identified in a population-based cohort of all cases diagnosed with breast cancer in Israel in 1987-1988 allowed the estimation of the population frequency of this phenomenon.
In the clinic-based series of 1191 carriers of mutations in BRCA1 or BRCA2 belonging to 567 families, 22 males and females (1.85%) from 17 different families (3.0%) were found to harbor two different mutations. These included 18 individuals (1.51%) who concomitantly carried the 185delAG BRCA1 and the 6174delT BRCA2 mutations and four individuals (0.34%) who carried the 5382insC BRCA1 and the 6174delT mutations. All individuals were heterozygote carriers and none had a double mutation of both founder mutations in the BRCA1 gene itself. Seven of the 16 double carrier women (46.7%) had a personal history of breast carcinoma, diagnosed at a mean age of 44.6, compared with 372/926 (40.2%) carriers of a single mutation diagnosed with a mean age at diagnosis of 48.1 [odds ratio (OR)=1.3, 95% confidence interval (CI) 0.4-4.0]. One case (6.7%) had a personal history of ovarian carcinoma diagnosed at the age of 53 compared with 55/926 (5.9%) of the women with single mutation (OR=1.1, CI=0.2-7.6). The frequency of double mutations in the population-based national breast cancer cohort was 2.2% of all carriers, and 0.3% of all breast cancer cases in the Ashkenazi population in the cohort. The mean age at diagnosis of breast cancer was younger in the carriers of two mutations.
Double carriers of mutations in the BRCA genes are rare and seem to be carrying a similar probability of developing breast and ovarian cancers as carriers of single mutations.
同时携带 BRCA1 和 BRCA2 基因致病性突变的个体中疾病的频率和特征尚不清楚。
数据来自 Clalit 健康服务国家家族癌症咨询服务数据库。该临床服务中推荐的先证者及其家庭成员通常会接受三种犹太创始人突变（BRCA1：185delAG、5382insC、BRCA2：6174delT）的检测。此外，在 1987-1988 年以色列所有诊断为乳腺癌的病例的基于人群的队列中发现的携带者，允许估计这种现象的人群频率。
在属于 567 个家庭的 1191 名携带 BRCA1 或 BRCA2 突变的携带者的临床系列中，来自 17 个不同家庭（3.0%）的 22 名男性和女性（1.85%）被发现携带两种不同的突变。其中包括 18 名个体（1.51%）同时携带 185delAG BRCA1 和 6174delT BRCA2 突变，4 名个体（0.34%）携带 5382insC BRCA1 和 6174delT 突变。所有个体均为杂合子携带者，且在 BRCA1 基因本身中均无两个创始人突变的双重突变。16 名双重携带者女性中有 7 人（46.7%）有乳腺癌个人病史，平均诊断年龄为 44.6 岁，而 926 名携带单个突变的携带者中有 372 人（40.2%）诊断为平均年龄为 48.1 岁[比值比（OR）=1.3，95%置信区间（CI）0.4-4.0]。1 例（6.7%）有卵巢癌个人病史，诊断年龄为 53 岁，而在 926 名携带单个突变的女性中，有 55 例（5.9%）有卵巢癌个人病史（OR=1.1，CI=0.2-7.6）。在基于人群的全国乳腺癌队列中，双重突变的频率为所有携带者的 2.2%，在队列中阿什肯纳兹人群所有乳腺癌病例中的频率为 0.3%。携带两种突变的个体的乳腺癌诊断年龄平均值更年轻。
BRCA 基因的双重突变携带者很少见，似乎与携带单个突变的携带者一样，有发展乳腺癌和卵巢癌的相似概率。
