Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
EMBO Mol Med. 2018 Sep;10(9). doi: 10.15252/emmm.201708552.
Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, and , were also functionally scrutinized, providing evidence of a tumorigenic role, for mutations in particular.
微卫星不稳定性 (MSI) 导致基因组中积累了大量的突变，主要是小的插入和缺失。MSI 结直肠癌 (CRC) 也比微卫星稳定 (MSS) 肿瘤含有更多的点突变，但它们尚未得到全面研究。为了确定受 MSI CRC 点突变影响的候选驱动基因，我们利用一种算法，根据突变意义对基因进行排名，同时纠正复制时间和基因表达。该算法利用了 24 个外显子组测序的散发性 MSI CRC 及其相应的正常样本的外显子试剂盒靶向区域的体细胞点突变数据，以及 12 个全基因组测序的散发性 MSI CRC 及其相应的正常样本。前 73 个基因在另外 93 个 MSI CRC 中进行了验证。MutSigCV 排名确定了几个已确立的 MSI CRC 驱动基因，并为先前提出的 CRC 候选基因提供了额外的证据，同时还列出了我们所知以前与 CRC 无关的基因。两个基因 和 也进行了功能研究，特别是为 基因突变提供了致癌作用的证据。
