Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors
Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors
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DOI：
10.1093/jnci/92.7.564
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发表时间：
2000-04-05
影响因子：
10.3
通讯作者：
Herman, JG
中科院分区：
文献类型：
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作者：
Esteller, M;Silva, JM;Herman, JG
背景：BRCA1基因中的遗传突变可能是遗传性乳腺癌的几乎一半。然而，尽管经常在BRCA1基因座和肿瘤中BRCA1蛋白的损失，但尚未报道BRCA1中的体细胞（获得的）突变。为了解决BRCA1是否被散发性肿瘤突变以外的途径灭活，我们分析了基因启动子区域高甲基化的作用。方法：通过甲基化特异性聚合酶链反应（PCR）在乳腺癌细胞系，异种移植物以及215个原代乳腺癌和卵巢癌中评估BRCA1启动子中的甲基化模式，BRCA1 RTA表达在细胞系中确定在细胞系中，并通过反向转录在细胞系中确定-pcr，p值是双面的。结果：发现BRCA1启动子在所有正常组织和测试的癌细胞系中都没有甲基化，但是，TAO乳腺癌异种移植物中存在的BRCA1启动子高甲基化NAS，这两种NA都损失了BRCA1转录本。 BRCA1启动子高甲基化AA中存在于84个未选择的原发性乳腺癌中的11个（13％）。 BRCA1甲基化与髓样（67％甲基化； P = .0002对导管）和粘液（55％甲基化； P = .0033相对于导管）亚型，这些亚型在BRCA1家族中的体现过高。在第二次系列的66个导管乳腺肿瘤中，LOH的45个肿瘤中有9个（20％）具有BRCA1高甲基化，而21个没有LOB ASS甲基化的21个（5％）（5％）（p = .15）。在卵巢肿瘤中，仅在LOH的肿瘤中发现BRCA1甲基化，其中4（31％）在13中，而没有LOH的18个（p = .02）。在其他肿瘤类型中，BRCA1启动子是未甲基化的。结论：通过启动子高甲基化对BRCA1基因的沉默发生在原发性乳腺癌和卵巢癌中，尤其是在LOH和特定的组织病理亚组中。这些发现支持该肿瘤抑制基因在散发性乳房和卵巢肿瘤发生中的作用。
Background: Inherited mutations in the BRCA1 gene may be responsible for almost half of inherited breast carcinomas. However, somatic (acquired) mutations in BRCA1 have not been reported, despite frequent loss of heterozygosity (LOH or loss of one copy of the gene) at the BRCA1 locus and loss of BRCA1 protein in tumors. To address whether BRCA1 may be inactivated by pathways other than mutations in sporadic tumors, we analyzed the role of hypermethylation of the gene's promoter region. Methods: Methylation patterns in the BRCA1 promoter were assessed in breast cancer cell lines, xenografts, and 215 primary breast and ovarian carcinomas by methylation-specific polymerase chain reaction (PCR), BRCA1 RTA expression was determined in cell lines and seven xenografts by reverse transcription-PCR, P values are two-sided. Results: The BRCA1 promoter was found to be unmethylated in all normal tissues and cancer cell lines tested, However, BRCA1 promoter hypermethylation nas present in tao breast cancer xenografts, both of which had loss of the BRCA1 transcript. BRCA1 promoter hypermethylation aas present in 11 (13%) of 84 unselected primary breast carcinomas. BRCA1 methylation was strikingly associated with the medullary (67% methylated; P = .0002 versus ductal) and mucinous (55% methylated; P = .0033 versus ductal) subtypes, which are overrepresented in BRCA1 families. In a second series of 66 ductal breast tumors informative for LOH nine (20%) of 45 tumors with LOH had BRCA1 hypermethylation, while one (5%) of 21 without LOB ass methylated (P = .15). In ovarian neoplasms, BRCA1 methylation was found only in tumors with LOH, four (31%) of 13 versus none of 18 without LOH (P = .02). The BRCA1 promoter was unmethylated in other tumor types. Conclusion: Silencing of the BRCA1 gene by promoter hypermethylation occurs in primary breast and ovarian carcinomas, especially in the presence of LOH and in specific histopathologic subgroups. These findings support a role for this tumor suppressor gene in sporadic breast and ovarian tumorigenesis.