Candidate driver genes in microsatellite-unstable colorectal cancer
Candidate driver genes in microsatellite-unstable colorectal cancer
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DOI：
10.1002/ijc.26167
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发表时间：
2012-04-01
影响因子：
6.4
通讯作者：
Aaltonen, Lauri A.
中科院分区：
文献类型：
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作者：
Alhopuro, Pia;Sammalkorpi, Heli;Aaltonen, Lauri A.
错配修复系统的缺陷会导致微卫星不稳定 (MSI)，这一特征在 15% 的结直肠癌 (CRC) 中观察到。驱动肿瘤发生的微卫星突变（通常是肿瘤抑制因子的失活）在 MSI 癌症中被选择并经常被检测到。在这里，我们评估了 790 个基因的微卫星重复中的体细胞突变，这些基因是根据 MSI CRC 中表达的减少以及长度相似的 6 个编码单核苷酸重复的存在而选择的。所有重复序列最初均在 30 个主要 MSI CRC 样本中进行测序，每当移码突变超过 20% 时，就会对另外 70 个样本进行测序。为了区分驾驶员突变和乘客突变，我们同样分析了 121 个内含子控制重复序列中移码突变的发生情况，并利用统计回归模型来确定所有类型重复序列（A/T 和 C/G，610 bp）的截止突变频率。除了几个已知的靶基因（包括 TGFBR2、ACVR2 和 MSH3）之外，还出现了 6 个新的候选驱动基因，它们比相同的对照重复序列具有更多的突变。 100份MSI CRC样本中，GLYR1的G8突变频率为51%，ABCC5的T9突变频率为47%，WDTC1的G8突变频率为43%，ROCK1的A8突变频率为33%，OR51E2的T8突变频率为30%，TCEB3的A8突变频率为28%。 GLYR1 的免疫组织化学染色揭示了携带双等位基因突变的肿瘤中蛋白质表达缺陷，支持了功能丧失的假说。这是一项大规模、公正的努力，旨在识别突变时可能有助于 MSI CRC 发展的基因。
Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in similar to 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6 similar to 10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 610 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development.