Bi-allelic inactivation of TCF1 in hepatic adenomas
Bi-allelic inactivation of TCF1 in hepatic adenomas
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DOI：
10.1038/ng1001
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发表时间：
2002-10-01
期刊：
影响因子：
30.8
通讯作者：
Zucman-Rossi, J
中科院分区：
文献类型：
--
作者：
Bluteau, O;Jeannot, E;Zucman-Rossi, J
肝腺瘤是有恶变风险的良性肿瘤。在全基因组搜索与肝腺瘤相关的杂合性丢失 (LOH) 时，我们发现十个腺瘤中有五个 12q 染色体缺失。在大多数情况下，12q 处的 LOH 是观察到的唯一反复发生的基因改变，表明该区域存在肿瘤抑制基因。 12q24 中定义了一个最小的共同缺失区域，其中包括编码肝细胞核因子 1 (HNF1；参考文献 1,2) 的基因 TCF1（转录因子 1）。 TCF1 杂合种系突变已在患有青少年 3 型成年发病糖尿病的个体中被发现（MODY3；参考文献 3）。在 16 个筛选的腺瘤中，有 10 个发现 TCF1 双等位基因失活，并且在 3 个受影响的个体中存在杂合种系突变。此外，正常肝脏中发生的 2 个分化良好的肝细胞癌 (HCC) 含有 30 个筛选的 HCC 的体细胞双等位基因突变。这些结果表明，TCF1的失活，无论是散发的还是与MODY3相关的，都是人类肝腺瘤发生的重要遗传事件，并且可能是某些HCC发展的早期步骤。
Liver adenomas are benign tumors at risk of malignant transformation. In a genome-wide search for loss of heterozygosity (LOH) associated with liver adenomas, we found a deletion in chromosome 12q in five of ten adenomas. In most cases, LOH at 12q was the only recurrent genetic alteration observed, suggesting the presence of a tumor-suppressor gene in that region. A minimal common region of deletion was defined in 12q24 that included the gene TCF1 (transcription factor 1), encoding hepatocyte nuclear factor 1 (HNF1; refs 1,2). Heterozygous germline mutations of TCF1 have been identified in individuals affected with maturity-onset diabetes of the young type 3 (MODY3; ref. 3). Bi-allelic inactivation of TCF1 was found in 10 of 16 screened adenomas, and heterozygous germline mutation were present in three affected individuals. Furthermore, 2 well-differentiated hepatocellular carcinomas (HCCs) occurring in normal liver contained somatic bi-allelic mutations of 30 screened HCCs. These results indicate that inactivation of TCF1, whether sporadic or associated with MODY3, is an important genetic event in the occurrence of human liver adenoma, and may be an early step in the development of some HCCs.