Satagopan Jaya M, Boyd Jeff, Kauff Noah D, Robson Mark, Scheuer Lauren, Narod Steven, Offit Kenneth
Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Clin Cancer Res. 2002 Dec;8(12):3776-81.
Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations.
A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer.
Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21% (95% CI, 13-41%) for a BRCA2 mutation.
The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.
迄今为止，已有多项研究利用家族数据或基于人群的先证者系列报道了因遗传性BRCA1和BRCA2突变导致的卵巢癌风险。与这两种方法相关的家族聚集可能会导致严重的确诊偏倚。为解决这一问题，我们采用了一种不涉及家族聚集的病例对照设计，以估计因BRCA1和BRCA2突变导致的卵巢癌终生发病风险。
共有382例自我认定为犹太裔且既往未诊断出乳腺癌的卵巢癌病例，来自两个基于医院的系列。在第一个系列中，确定了197例1986年至2000年间在纪念斯隆凯特琳癌症中心诊断和治疗的自我认定为犹太裔且无乳腺癌病史的浸润性上皮性卵巢癌病例。在第二个系列中，1995年至1996年在北美和以色列的11个中心进行的一项研究中，确定了185例无既往乳腺癌病史的犹太裔浸润性上皮性卵巢癌患者。对照组是来自美国国立癌症研究所的研究人员在华盛顿特区地区对大量犹太裔基因分型志愿者进行的一项大型研究中，3434名无任何乳腺癌或卵巢癌病史的犹太女性。对病例和对照进行了三种阿什肯纳兹犹太族始祖突变的基因分型，即BRCA1中的185delAG和5382insC以及BRCA2中的6174delT。使用优势比、对照组中的突变患病率以及从监测、流行病学和最终结果数据库获得的美国普通人群中的卵巢癌发病率，并根据乳腺癌后卵巢癌的发病率进行调整，来估计终生发病风险。
在147例病例和62例对照中发现了突变。BRCA1突变在70岁时的估计发病风险为37%（95%置信区间，25 - 71%），BRCA2突变在70岁时的估计发病风险为21%（95%CI，13 - 41%）。
BRCA1突变的终生发病风险低于使用有多个患病成员的家族数据获得的估计值，但高于一些基于人群的先证者系列的估计值。BRCA2突变的终生发病风险估计值在一些基于家族数据的研究报告的范围内。这些结果可能对携带这些始祖突变的女性的临床咨询、手术干预和筛查建议有影响。
