Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma

Ming Hui Yang, Chia Hung Yen, Yen Fu Chen, Cheng Chieh Fang, Chung Hsien Li, Kuo Jui Lee, Yi Hsiung Lin, Chien Hui Weng, Tze Tze Liu, Shiu Feng Huang, Bin Tean Teh, Yi Ming Arthur Chen

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Abstract

Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC). The overexpression of Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is observed in various tumors, including HCC; and the frequent PREX2 mutations in melanoma are associated with invasiveness. We sought to identify somatic mutations and the functional changes in mutational signatures of PREX2. Genomic DNA sequencing was performed in 68 HCC samples with three types of hepatitis viral infection status: HBs Ag-positive, anti-HCV Ab-positive, and negative for any hepatitis B or C markers. Stabilities and interactions of proteins as well as cell proliferation and migration were evaluated. Fourteen non-silent point mutations in PREX2 were detected, with 16 of 68 HCC patients harboring at least one non-silent mutation. All mutant forms of PREX2, except for K400f, had an extended half-life compared with wild-type PREX2. Moreover, only the half-life of S1113R was twice that of the wild-type. PREX2 mutant-S1113R also promoted migration and activated the AKT pathway as well as impaired HectH9-mediated ubiquitination. Our study identified a gain-of-function mutation of PREX2 – S1113R in HCC. Such mutation enhanced PREX2 protein stability, promoted cell proliferation, and was associated with aggressiveness of HCC.

Original languageEnglish
Article number2552
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Cite this

Yang, M. H., Yen, C. H., Chen, Y. F., Fang, C. C., Li, C. H., Lee, K. J., Lin, Y. H., Weng, C. H., Liu, T. T., Huang, S. F., Teh, B. T., & Chen, Y. M. A. (2019). Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma. Scientific Reports, 9(1), [2552]. https://doi.org/10.1038/s41598-018-36810-5