Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.


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.

DOI: 10.1038/ng.2983

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@article{Wang2014WholegenomeSA, title={Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.}, author={Kai Wang and Siu Tsan Yuen and Jiangchun Xu and Siu Po Lee and Helen H N Yan and Stephanie Tao Shi and Hoi Cheong Siu and Shibing Deng and Kent Man Chu and Simon Law and Kok Hoe Chan and Annie S Y Chan and Wai Yin Tsui and Siu Lun Ho and Anthony Kin Wang Chan and Jonathan L K Man and Valentina Foglizzo and Man Kin Ng and April S Chan and Yick Pang Ching and Grace H W Cheng and Tao Xie and Julio Fern{\'a}ndez and Vivian S W Li and Hans Clevers and Paul A. Rejto and Mao Mao and Suet Yi Leung}, journal={Nature genetics}, year={2014}, volume={46 6}, pages={573-82} }