Baldwin R L, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, Karlan B Y
Division of Gynecologic Oncology, The Burns and Allen Research Institute. Cedars-Sinai Medical Center, Los Angeles, California 90048 USA.
Cancer Res. 2000 Oct 1;60(19):5329-33.
There is a clear association between germ-line BRCA1 mutations and inherited ovarian cancer; however, the association between BRCA1 mutations and sporadic ovarian cancer remains ambiguous. The frequency of BRCA1 promoter hypermethylation as an epigenetic means of BRCA1 inactivation was determined for a large, population-based cohort of ovarian cancer patients. BRCA1 promoter hypermethylation was determined by methylation-specific restriction digestion of tumor DNA, followed by Southern blot analysis and confirmed by methylation-specific PCR. BRCA1 promoter hypermethylation was observed in 12 of 98 ovarian tumors. BRCA1 methylation status of the primary tumor was conserved in six recurrent tumors after interim chemotherapy. None of the 12 tumors with BRCA1 promoter hypermethylation demonstrated BRCA1 protein expression by immunohistochemistry. BRCA1 methylation was only seen in ovarian cancer patients without a family history suggestive of a breast/ ovarian cancer syndrome. Therefore, the 12 BRCA1 methylated tumors represented 15% (12 of 81) of the sporadic cancers analyzed in this study. Although the clinical significance of BRCA1 promoter hypermethylation is yet to be determined, promoter hypermethylation may be an alternative to mutation in causing the inactivation of the BRCA1 tumor suppressor gene in sporadic ovarian cancer.
生殖系BRCA1突变与遗传性卵巢癌之间存在明确关联；然而，BRCA1突变与散发性卵巢癌之间的关联仍不明确。针对一大群基于人群的卵巢癌患者队列，确定了作为BRCA1失活表观遗传手段的BRCA1启动子高甲基化频率。通过对肿瘤DNA进行甲基化特异性限制性消化，随后进行Southern印迹分析来确定BRCA1启动子高甲基化，并通过甲基化特异性PCR进行确认。在98个卵巢肿瘤中有12个观察到BRCA1启动子高甲基化。在中期化疗后的6个复发性肿瘤中，原发性肿瘤的BRCA1甲基化状态得以保留。12个BRCA1启动子高甲基化的肿瘤中，通过免疫组织化学均未检测到BRCA1蛋白表达。BRCA1甲基化仅在无乳腺癌/卵巢癌综合征家族史的卵巢癌患者中出现。因此，12个BRCA1甲基化肿瘤占本研究分析的散发性癌症的15%（81个中的12个）。尽管BRCA1启动子高甲基化的临床意义尚待确定，但启动子高甲基化可能是散发性卵巢癌中导致BRCA1肿瘤抑制基因失活的一种替代突变的方式。
