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Gut. 2015 Apr;64(4):636-45. doi: 10.1136/gutjnl-2013-306620. Epub 2014 Jun 20.

Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer.

Author information

1
Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
2
Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Beijing Genomics Institute at Shenzhen, Shenzhen, China.
3
Department of Surgery, The Chinese University of Hong Kong, Hong Kong.
4
Beijing Genomics Institute at Shenzhen, Shenzhen, China.
5
Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
6
Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
7
Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
8
Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
9
Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong.

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.

KEYWORDS:

COLONIC NEOPLASMS

PMID:
24951259
PMCID:
PMC4392212
DOI:
10.1136/gutjnl-2013-306620
[Indexed for MEDLINE]
Free PMC Article
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