Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
- 11 May 2014
- journal article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 46 (6), 573-582
- https://doi.org/10.1038/ng.2983
Abstract
Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.Keywords
This publication has 76 references indexed in Scilit:
- Integrated genomic characterization of endometrial carcinomaNature, 2013
- Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexityNature Genetics, 2013
- A Landscape of Driver Mutations in MelanomaCell, 2012
- Comprehensive molecular characterization of human colon and rectal cancerNature, 2012
- CREST maps somatic structural variation in cancer genomes with base-pair resolutionNature Methods, 2011
- A comprehensive catalogue of somatic mutations from a human cancer genomeNature, 2009
- A ROCK inhibitor permits survival of dissociated human embryonic stem cellsNature Biotechnology, 2007
- Patterns of somatic mutation in human cancer genomesNature, 2007
- Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progressionLaboratory Investigation, 2004
- Statistical significance for genomewide studiesProceedings of the National Academy of Sciences of the United States of America, 2003