Berchuck A, Heron K A, Carney M E, Lancaster J M, Fraser E G, Vinson V L, Deffenbaugh A M, Miron A, Marks J R, Futreal P A, Frank T S
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Clin Cancer Res. 1998 Oct;4(10):2433-7.
Germline mutations in the BRCA1 tumor suppressor gene are thought to be the most common cause of hereditary ovarian cancer. The aim of this study was to explore further the role of BRCA1 alterations in the development of ovarian cancers. We sought to determine whether somatic BRCA1 mutations are ever present in ovarian cancers and whether mutation is always accompanied by loss of the wild-type allele. The entire coding region and intronic splice sites of BRCA1 were sequenced using genomic DNA samples from 103 unselected ovarian cancers. Thirteen clearly deleterious BRCA1 mutations and two variants of uncertain significance were found. Blood DNA was available in all but two cases and demonstrated that 4 of 13 mutations and both variants of uncertain significance were germline alterations, whereas in seven cases the mutation was a somatic change present only in the cancer. Using four microsatellite markers, loss of heterozygosity at the BRCA1 locus was found in all 15 ovarian cancers with BRCA1 sequence alterations, compared with only 58% of ovarian cancers that did not have BRCA1 mutations. BRCA1-associated ovarian cancers were characterized by serous histology and moderate histological grade. These data confirm prior reports suggesting that germline mutations in BRCA1 are present in about 5% of women with ovarian cancer. In addition, somatic mutations in BRCA1 occur in the development of some sporadic cases. The finding that both germline and somatic BRCA1 mutations are accompanied by loss of heterozygosity, suggests that loss of this tumor suppressor gene is a critical event in the development of these cancers.
BRCA1肿瘤抑制基因的种系突变被认为是遗传性卵巢癌最常见的病因。本研究的目的是进一步探讨BRCA1改变在卵巢癌发生发展中的作用。我们试图确定卵巢癌中是否存在体细胞BRCA1突变，以及突变是否总是伴随着野生型等位基因的缺失。使用来自103例未经选择的卵巢癌的基因组DNA样本对BRCA1的整个编码区和内含子剪接位点进行测序。发现了13个明显有害的BRCA1突变和2个意义不明确的变异。除2例病例外，其余所有病例均有血液DNA，结果显示13个突变中的4个以及2个意义不明确的变异均为种系改变，而在7例病例中，突变是仅存在于肿瘤中的体细胞变化。使用4个微卫星标记，在所有15例有BRCA1序列改变的卵巢癌中均发现BRCA1基因座杂合性缺失，而在没有BRCA1突变的卵巢癌中这一比例仅为58%。与BRCA1相关的卵巢癌具有浆液性组织学特征和中等组织学分级。这些数据证实了先前的报道，即约5%的卵巢癌女性存在BRCA1种系突变。此外，BRCA1体细胞突变发生在一些散发性病例的发展过程中。种系和体细胞BRCA1突变均伴有杂合性缺失这一发现表明，该肿瘤抑制基因的缺失是这些癌症发生发展中的关键事件。
