外显子组测序鉴定肝细胞癌的驱动基因。

Identification of driver genes in hepatocellular carcinoma by exome sequencing.

机构信息

Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.

出版信息

Hepatology. 2013 Nov;58(5):1693-702. doi: 10.1002/hep.26540. Epub 2013 Sep 24.

UNLABELLED

Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma (HCC). As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in HCC. We performed whole-exome sequencing on 87 HCCs and matched normal adjacent tissues to an average coverage of 59×. The overall mutation rate was roughly two mutations per Mb, with a median of 45 nonsynonymous mutations that altered the amino acid sequence (range, 2-381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%); CTNNB1 (10%); KEAP1 (8%); C16orf62 (8%); MLL4 (7%); and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine-rich repeat-containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors.

CONCLUSION

The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of HCC.

未注明

特定驱动基因中的遗传改变导致细胞途径中断，是肝细胞癌 (HCC) 发生和进展的关键事件。作为个体化癌症治疗的前提条件，我们试图描述 HCC 中复发性体细胞突变的特征。我们对 87 例 HCC 和匹配的正常相邻组织进行了全外显子组测序，平均覆盖率为 59×。总体突变率约为每 Mb 两个突变，中位数为 45 个改变氨基酸序列的非同义突变（范围为 2-381）。我们发现几个转录水平较高的基因中存在反复突变：TP53（18%）；CTNNB1（10%）；KEAP1（8%）；C16orf62（8%）；MLL4（7%）；和 RAC2（5%）。受显著影响的基因家族包括核苷酸结合域和富含亮氨酸重复序列家族、钙通道亚基和组蛋白甲基转移酶。特别是，MLL 家族的组蛋白 H3 赖氨酸 4 甲基转移酶在 20%的肿瘤中发生突变。