Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma

doi:10.1038/ng.2984

. 2014 Jun;46(6):583-7.

doi: 10.1038/ng.2984. Epub 2014 May 11.

Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma

Miwako Kakiuchi¹, Takashi Nishizawa², Hiroki Ueda³, Kengo Gotoh³, Atsushi Tanaka⁴, Akimasa Hayashi⁴, Shogo Yamamoto⁵, Kenji Tatsuno⁵, Hiroto Katoh⁶, Yoshiaki Watanabe⁷, Takashi Ichimura⁴, Tetsuo Ushiku⁴, Shinichi Funahashi², Keisuke Tateishi⁸, Ikuo Wada⁹, Nobuyuki Shimizu⁹, Sachiyo Nomura⁹, Kazuhiko Koike⁸, Yasuyuki Seto⁹, Masashi Fukayama⁴, Hiroyuki Aburatani⁵, Shumpei Ishikawa¹⁰

Affiliations

¹ 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Forerunner Pharma Research Co., Ltd., Tokyo, Japan.
³ Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
⁴ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan.
⁶ Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
⁷ Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan.
⁸ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁹ Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁰ 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [3] Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

PMID: 24816255
DOI: 10.1038/ng.2984

Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma

Miwako Kakiuchi et al. Nat Genet. 2014 Jun.

. 2014 Jun;46(6):583-7.

doi: 10.1038/ng.2984. Epub 2014 May 11.

Authors

Affiliations

¹ 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Forerunner Pharma Research Co., Ltd., Tokyo, Japan.
³ Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
⁴ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan.
⁶ Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
⁷ Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan.
⁸ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁹ Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁰ 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [3] Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

PMID: 24816255
DOI: 10.1038/ng.2984

Abstract

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.

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Comment in

Genetics: revealing the genomic landscape of gastric cancer.
Ray K. Ray K. Nat Rev Gastroenterol Hepatol. 2014 Jul;11(7):394. doi: 10.1038/nrgastro.2014.86. Epub 2014 May 27. Nat Rev Gastroenterol Hepatol. 2014. PMID: 24860930 No abstract available.

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References

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1. Nat Biotechnol. 2012 May;30(5):413-21 - PubMed
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[1] Bioinformatics. 2009 Jul 15;25(14):1754-60 - PubMed

[2] Bioinformatics. 2009 Jul 15;25(14):1754-60 - PubMed

[3] Nat Biotechnol. 2012 May;30(5):413-21 - PubMed

[4] Nat Biotechnol. 2012 May;30(5):413-21 - PubMed

[5] Nature. 1998 Jul 16;394(6690):295-9 - PubMed

[6] Nature. 1998 Jul 16;394(6690):295-9 - PubMed

[7] J Cell Sci. 2004 Mar 15;117(Pt 8):1301-12 - PubMed

[8] J Cell Sci. 2004 Mar 15;117(Pt 8):1301-12 - PubMed

[9] World J Gastroenterol. 2012 Mar 7;18(9):896-904 - PubMed

[10] World J Gastroenterol. 2012 Mar 7;18(9):896-904 - PubMed

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Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma

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Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma

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