Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma

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.

Integrative analysis of highly mutated genes in hepatitis B virus‐related hepatic carcinoma

“…Among these identified highly mutated genes, TP53, TERT, PEEX2, CTNNB1, and AXIN1 in HCC, especially in HBV-related HCC, have been investigated, and the published studies showed that these mutated genes played very important roles in the development of HCC. 10,11,18,21 In addition, consistent with the published studies, we found that COL11A1, RB1, MUC16, and PCLO, which have been detected by next-generation sequencing technology, 13,21-23 including whole genome sequencing and whole-exome sequencing by different groups, are also found to be associated with HCC in our research. However, the role of other mutated genes, including ABCA13, COL11A1, and COL12A1 as shown in Figure 2A, in HBV-related HCC, has not been well clarified and needs to be investigated in future studies.…”

“…We identified 78 highly mutated genes that associated with HBV‐related HCC, and the results were further validated by using the LICA‐CN cohort in ICGC database. Among these identified highly mutated genes, TP53, TERT, PEEX2, CTNNB1, and AXIN1 in HCC, especially in HBV‐related HCC, have been investigated, and the published studies showed that these mutated genes played very important roles in the development of HCC . In addition, consistent with the published studies, we found that COL11A1, RB1, MUC16, and PCLO, which have been detected by next‐generation sequencing technology, including whole genome sequencing and whole‐exome sequencing by different groups, are also found to be associated with HCC in our research.…”

“…For example, the mutation of TERT in the promoter region could increase the expression of TERT gene . PREX2 gene mutation could enhance the stability of PREX2 protein . In addition, specific CTNNB1 mutations could enhance the activity of ß‐catenin that associated with malignant transformation in HCC .…”

“…Ho et al report that TSC1/2 mutations contribute to the disruption of the downstream mTOR activity and lead to the more aggressive behavior of HCC cells . In addition, special mutations in PREX2 gene are shown to have the capability of enhancing PREX2 protein stability and promoting cell proliferation . TP53 mutations are observed to be related to the chemotherapy resistance, tumor recurrence, and decreased overall survival (OS) of HCC patients .…”

“…15 In addition, special mutations in PREX2 gene are shown to have the capability of enhancing PREX2 protein stability and promoting cell proliferation. 18 TP53 mutations are observed to be related to the chemotherapy resistance, tumor recurrence, and decreased overall survival (OS) of HCC patients. 19 Besides these, the study from Ye et al shows that RET mutations are linked to poor disease free survival (DFS) and OS in patients with HCC.…”