Takahashi H, Chiu H C, Bandera C A, Behbakht K, Liu P C, Couch F J, Weber B L, LiVolsi V A, Furusato M, Rebane B A, Cardonick A, Benjamin I, Morgan M A, King S A, Mikuta J J, Rubin S C, Boyd J
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Philadelphia, Pennsylvania 19104, USA.
Cancer Res. 1996 Jun 15;56(12):2738-41.
Inherited mutations in the recently discovered BRCA2 gene are believed to be responsible for a significant fraction of early-onset hereditary breast cancers. Unlike BRCA1, however, which confers a high risk to both breast and ovarian cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian cancer. Numerous allelotype studies indicate that allelic deletions Including the BRCA2 locus on chromosome 13q are common in ovarian cancers in general, suggesting that somatic mutations of this gene may be involved in sporadic ovarian tumorigenesis. The purpose of this study was to test the hypothesis that germline or somatic mutations of BRCA2 are associated with hereditary and/or sporadic ovarian cancers, respectively. The entire 10.2-kb coding region of BRCA2 was screened for mutations in 130 consecutive ovarian tumors, the only selection criterion being a pathological diagnosis of epithelial ovarian carcinoma. Loss of heterozygosity at markers flanking BRCA2 was observed in 56% of the tumors. Four germline mutations and two somatic mutations were identified; two of the germline mutations are recurrent, having been previously described. Remarkably, the patients with germline mutations were late-onset cases with no medical or family histories suggestive of hereditary cancer. These data suggest that mutations of BRCA2 are rare in sporadic ovarian cancers, and that the proportion of ovarian cancers resulting from hereditary predisposition may be higher than previously suspected based on estimates derived from studies of highly penetrant genetic loci.
最近发现的BRCA2基因的遗传性突变被认为是导致相当一部分早发性遗传性乳腺癌的原因。然而，与BRCA1不同，BRCA1会使患乳腺癌和卵巢癌的风险都很高，在与BRCA2相关的家族中，卵巢癌的发病率似乎要低得多，这使得BRCA2与遗传性卵巢癌的相关性存在不确定性。大量的等位基因分型研究表明，包括13号染色体q臂上BRCA2基因座在内的等位基因缺失在一般卵巢癌中很常见，这表明该基因的体细胞突变可能参与散发性卵巢肿瘤的发生。本研究的目的是检验以下假设：BRCA2的种系或体细胞突变分别与遗传性和/或散发性卵巢癌相关。对130例连续的卵巢肿瘤的BRCA2基因整个长达10.2kb的编码区进行了突变筛查，唯一的选择标准是上皮性卵巢癌的病理诊断。在56%的肿瘤中观察到BRCA2侧翼标记的杂合性缺失。鉴定出4种种系突变和2种体细胞突变；其中2种种系突变是复发性的，以前已有描述。值得注意的是，种系突变患者为晚发病例，没有提示遗传性癌症的病史或家族史。这些数据表明，BRCA2突变在散发性卵巢癌中很少见，而且基于对高穿透性基因座的研究估计，遗传性易感性导致的卵巢癌比例可能高于先前的怀疑。
