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ABSTRACT: Background
Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication.Objective
To identify recurrent somatic mutations with prognostic significance in patients with CRC.Method
Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases.Results
Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6-14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study.Conclusions
The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging.
SUBMITTER: Yu J
PROVIDER: S-EPMC4392212 | biostudies-literature | 2015 Apr
REPOSITORIES: biostudies-literature
Yu Jun J Wu William K K WK Li Xiangchun X He Jun J Li Xiao-Xing XX Ng Simon S M SS Yu Chang C Gao Zhibo Z Yang Jie J Li Miao M Wang Qiaoxiu Q Liang Qiaoyi Q Pan Yi Y Tong Joanna H JH To Ka F KF Wong Nathalie N Zhang Ning N Chen Jie J Lu Youyong Y Lai Paul B S PB Chan Francis K L FK Li Yingrui Y Kung Hsiang-Fu HF Yang Huanming H Wang Jun J Sung Joseph J Y JJ
Gut 20140620 4
<h4>Background</h4>Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication.<h4>Objective</h4>To identify recurrent somatic mutations with prognostic significance in patients with CRC.<h4>Method</h4>Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurren ...[more]