46, 573–582 (2014)
Received 01 August 2013
Accepted 18 April 2014
Published online 11 May 2014
Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA.Kai Wang, Siu Tsan Yuen, ・・・・Hans Clevers, Mao Mao, Suet Yi Leung
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.
- Published online
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.Miwako Kakiuchi,Takashi Nishizawa,Hiroki Ueda,・・・ Hiroyuki Aburatani, Shumpei Ishikawa
Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction. We performed whole-exome sequencing on 30 DGC cases and found recurrent RHOA nonsynonymous mutations. With validation sequencing of an additional 57 cases, RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein. These positions are highly conserved among RHO family members, and Tyr42 and Arg5 are located outside the guanine nucleotide–binding pocket. Several lines of functional evidence indicated that mutant RHOA works in a gain-of-function manner. Comparison of mutational profiles for the major gastric cancer subtypes showed that RHOA mutations occur specifically in DGCs, the majority of which were histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa. Our findings identify a potential therapeutic target for this poor-prognosis subtype of gastric cancer with no available molecularly targeted drugs.