Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion.
Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion.
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先前的研究已经确定了结直肠腺癌中的复发性致癌突变，并调查了11个受影响个体的突变的蛋白质编码基因的外显子，我们报告了9个结直肠癌的全基因组测序组织平均分别为30.7×和31.9倍。尽管TCF7L2编码在有色癌中使用β-catenin指导的TCF4，但融合缺乏TCF4β-catenin –结合结构域的TCF4β-caten蛋白。 VTI1A-TCF7L2用于使用RNA干扰介导的敲低的锚固生长，该研究显示了结直肠癌的基因组重排水平，这可以导致必要的基因融合和其他致癌事件。
Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin–binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.