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Nat Genet. 2014 Jun;46(6):573-82. doi: 10.1038/ng.2983. Epub 2014 May 11.

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

Author information

1
1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2].
2
1] Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. [2].
3
1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2] [3].
4
External Research Solutions, Pfizer Worldwide Research and Development, San Diego, California, USA.
5
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
6
Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA.
7
Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
8
Division of Stem Cell Biology and Developmental Genetics, Medical Research Council (MRC) National Institute for Medical Research, London, UK.
9
Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong.
10
Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands.

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.

Comment in

PMID:
24816253
DOI:
10.1038/ng.2983
[Indexed for MEDLINE]

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