@article{61c89111f73a41809b9b47a13f40a02f,
title = "Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer",
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.",
author = "Kai Wang and Yuen, {Siu Tsan} and Jiangchun Xu and Lee, {Siu Po} and Yan, {Helen H.N.} and Shi, {Stephanie T.} and Siu, {Hoi Cheong} and Shibing Deng and Chu, {Kent Man} and Simon Law and Chan, {Kok Hoe} and Chan, {Annie S.Y.} and Tsui, {Wai Yin} and Ho, {Siu Lun} and Chan, {Anthony K.W.} and Man, {Jonathan L.K.} and Valentina Foglizzo and Ng, {Man Kin} and Chan, {April S.} and Ching, {Yick Pang} and Cheng, {Grace H.W.} and Tao Xie and Julio Fernandez and Li, {Vivian S.W.} and Hans Clevers and Rejto, {Paul A.} and Mao Mao and Leung, {Suet Yi}",
note = "Funding Information: We thank J. Shen for assistance with bioinformatics and clinicians at the Hong Kong Hospital Authority for clinical care. We thank Illumina for performing whole-genome sequencing, TruSeq and array experiments and the Centre for Genomics Sciences at the University of Hong Kong for other sequencing services. Funding for the whole-genome sequencing study and associated validation was provided by Pfizer. Funding for the methylation analysis was provided by the Research Grants Council of the Hong Kong Special Administrative Region (General Research Fund grant HKU7719/10M). Funding for the functional assays was provided by a donation from S.T. Pan.",
year = "2014",
month = jun,
doi = "10.1038/ng.2983",
language = "English",
volume = "46",
pages = "573--582",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "6",
}