Epigenetic silencing contributes to frequent toss of the fragile histidine triad tumour suppressor in basal cell carcinomas
Epigenetic silencing contributes to frequent toss of the fragile histidine triad tumour suppressor in basal cell carcinomas
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DOI：
10.1111/j.1365-2133.2006.07433.x
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发表时间：
2006-12-01
影响因子：
10.3
通讯作者：
Ballhausen, W. G.
中科院分区：
文献类型：
--
作者：
Goldberg, M.;Rummelt, C.;Ballhausen, W. G.
背景 大量暴露于紫外线辐射与基底细胞癌 (BCC) 的遗传改变有关，基底细胞癌约占技能性癌症的 75%。 目的 由于最近的数据表明脆性组氨酸三联体 (FHIT) 基因产物参与 DNA 损伤反应，我们希望解决该肿瘤抑制因子的功能性缺失是否参与 BCC 的发展。我们的研究重点是 FHIT 基因的表观遗传失活。方法对 17 例 BCC 患者的石蜡包埋标本进行甲基化特异性聚合酶链反应 (MSP)、FHIT 基因的联合亚硫酸氢盐依赖性限制性分析 (COBRA) 及其产物的免疫组织化学分析。结果我们首次报告通过免疫染色 100% 的 BCC 为 FHIT 阴性。 FHIT 启动子的异常甲基化发生在很大一部分 BCC 中。 MSP 在 9 个眼周 BCC 中的 9 个 (100%) 和来自其他身体区域的 8 个 BCC 中的 6 个 (75%) 中检测到 FHIT/FRA3B 基因座的高甲基化。 COBRA 得出了类似的结果，证实所分析的 17 个 BCC 中约有 88% 存在 FHIT 基因的表观遗传沉默。免疫组织化学证实了 FHIT 蛋白的丢失，证实启动子高甲基化与基因表达丢失相关。结论我们已经确定 FHIT 肿瘤抑制基因的表观遗传沉默是一种频繁的失活机制，可能导致 BCC DNA 损伤反应的功能缺陷。
Background Extensive exposure to ultraviolet radiation is associated with genetic alterations in basal cell carcinomas (BCCs), which represent some 75% of skill cancers.Objectives As recent data suggested the fragile histidine triad (FHIT) gene product to participate in DNA damage responses we wished to address whether functional deletion of this tumour suppressor participates in the development of BCC. Our study focused on epigenetic inactivation of the FHIT gene.Methods Paraffin-embedded specimens from 17 patients with BCC were available for methylation-specific polymerase chain reaction (MSP), combined bisulphite-dependent restriction analysis (COBRA) of the FHIT gene and immunohistochemistry of its product.Results We report for the first time that 100% of BCCs are negative for FHIT by immunostaining. Aberrant methylation of the FHIT promoter occurred in a significant portion of BCCs. MSP detected hypermethylation of the FHIT/FRA3B locus in nine of nine (100%) periocular BCCs and in six of eight (75%) BCCs from other body regions. COBRA yielded similar results, confirming that some 88% of the 17 BCCs analysed harbour epigenetic silencing of the FHIT gene. Loss of FHIT protein was demonstrated immunohistochemically, confirming that promoter hypermethylation correlated with loss of gene expression.Conclusions We have identified epigenetic silencing of the FHIT tumour suppressor gene as a frequent inactivation mechanism which is likely to contribute to functional deficiencies in DNA damage response of BCCs.