Expression of BRCA I protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA I gene
Expression of BRCA I protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA I gene
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DOI：
10.1002/path.1507
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发表时间：
2004-02-01
影响因子：
7.3
通讯作者：
Konishi, I
中科院分区：
文献类型：
--
作者：
Wang, C;Horiuchi, A;Konishi, I
BRCA1是一种假定的肿瘤抑制基因，负责遗传性卵巢癌综合征。为了阐明BRCA 1可能参与散发性卵巢肿瘤的发生，本研究分析了BRCA 1蛋白在正常卵巢表面上皮和119例上皮性卵巢肿瘤（19例良性，24例交界性和76例恶性肿瘤）中的免疫组化表达。用3个微卫星标记检测BRCA 1基因的杂合性丢失（洛），分析BRCA 1基因的表达与BRCA 1基因变异的关系。BRCA1启动子的甲基化也通过甲基化特异性PCR进行了分析。在同一肿瘤中显示BRCA 1蛋白异质性表达的卵巢癌中，使用显微切割技术分析洛和甲基化状态。最后，分析BRCA 1表达或其基因改变与临床病理参数和患者生存期的关系。卵巢表面上皮细胞表达BRCA1蛋白。BRCA1的表达在16%的良性肿瘤、38%的交界性肿瘤和72%的癌中降低。BRCA 1的洛缺失在良性肿瘤中未发现，在交界性肿瘤中为15%，在恶性肿瘤中为66%。BRCA1甲基化在良性或交界性肿瘤中未检测到，但在31%的癌中存在。BRCA1表达减少与基因甲基化的存在相关。BRCA 1甲基化和洛在浆液性癌中的发生率高于其他类型。在三个浆液性癌中的一个显示BRCA1的异质性表达，BRCA1阳性的边缘样肿瘤细胞是LOH阳性和甲基化阴性，而相邻的BRCA1阴性癌细胞是LOH阳性和甲基化阳性。乳腺癌患者的预后与BRCA 1表达和基因状态无关。这些发现表明，BRCA 1蛋白表达的减少沿着BRCA 1基因的遗传和表观遗传改变在散发性卵巢癌的发展中起重要作用，特别是浆液性卵巢癌。版权所有（C）2004约翰威利父子有限公司。
BRCA1 is a putative tumour suppressor gene responsible for a hereditary ovarian cancer syndrome. To clarify the possible involvement of BRCA1 in the development of sporadic ovarian neoplasms, this study analysed the immunohistochemical expression of BRCA1 protein in normal ovarian surface epithelium and 119 epithelial ovarian tumours (19 benign, 24 borderline, and 76 malignant tumours). Loss of heterozygosity (LOH) of BRCA1 was examined using three microsatellite markers to analyse the relationship between BRCA1 expression and alterations of the BRCA1 gene. Methylation of the BRCA1 promoter was also analysed by methylation-specific PCR. In ovarian carcinomas showing heterogeneous expression of BRCA1 protein in the same tumour, LOH and methylation status were analysed using microdissection techniques. Finally, the relationship of BRCA1 expression or its genetic alteration to clinicopathological parameters and patient survival was analysed. Ovarian surface epithelial cells expressed BRCA1 protein. Decreased expression of BRCA1 was found in 16% of benign tumours, 38% of borderline tumours, and 72% of carcinomas. LOH of BRCA1 was demonstrated in no benign tumours, 15% of borderline tumours, and 66% of carcinomas. Methylation of BRCA1 was not detected in benign or borderline tumours, but was present in 31% of carcinomas. Reduced expression of BRCA1 correlated with the presence of gene methylation. The frequency of BRCA1 methylation and LOH was higher in serous carcinomas than in other types. In one of the three serous carcinomas that showed heterogeneous expression of BRCA1, BRCA1-positive borderline-like tumour cells were LOH-positive and methylation-negative, whereas adjacent BRCA1-negative carcinoma cells were LOH-positive and methylation-positive. The prognosis of carcinoma patients did not correlate with BRCA1 expression or genetic status. These findings suggest that reduced expression of BRCA1 protein along with genetic and epigenetic changes of the BRCA1 gene play an important role in the development of sporadic ovarian carcinomas, particularly those of serous histology. Copyright (C) 2004 John Wiley Sons, Ltd.