PREX2

Overview

PREX2 (Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2) encodes a guanine nucleotide exchange factor (GEF) for RAC1 that also interacts with and negatively regulates PTEN. Somatic mutations in PREX2 were identified as a significantly mutated gene in melanoma by whole-genome sequencing, with functional experiments demonstrating oncogenic activity of mutant PREX2 in melanocytes. PREX2 alterations represent one of the most frequent recurrent mutational events in melanoma beyond BRAF and NRAS.

Alterations observed in the corpus

  • PREX2 significantly mutated in melanoma: 11/25 (44%) discovery tumors carry at least one non-synonymous mutation, including 4 nonsense truncations; 14% non-synonymous mutation frequency confirmed in 107-sample extension cohort PMID:22622578
  • Complex structural rearrangements and high-level amplification of PREX2 detected in acral melanoma ME032 PMID:22622578
  • Ectopic expression of 3 truncated PREX2 variants and the G844D point mutant significantly accelerated in vivo tumor formation in PMEL-NRAS* melanocytes compared to wild-type PREX2 or GFP controls PMID:22622578
  • p.Arg297Cys and p.Glu1295Lys mutations (alleles previously reported in melanoma, cutaneous SCC, and head and neck cancer); encodes a Rac exchange factor that inhibits PTEN; functionally connected to recurrent PTEN 10q23.3 deletions in Sézary syndrome PMID:26551667
  • Two novel nonsynonymous events (S1167T, A355T) in acral melanoma; not previously reported as recurrent in melanoma, although S1167N was reported in a cutaneous melanoma metastasis PMID:28373299

Cancer types (linked)

  • SKCM (Melanoma): 11/25 discovery WGS tumors; 14% in 107-sample extension cohort; mutations distributed across the gene, not confined to a single hotspot PMID:22622578

Co-occurrence and mutual exclusivity

  • PREX2 mutations co-occur with BRAF V600E (which was present in 16/25 melanomas) and NRAS mutations (9/25), as mutations are not reported as mutually exclusive with either PMID:22622578
  • PREX2 is a known PTEN-interacting protein and negative regulator; PTEN was recurrently disrupted by structural rearrangements in 4/25 tumors in the same cohort PMID:22622578

Therapeutic relevance

  • PREX2 mutations represent a novel, recurrent genomic event in melanoma that may serve as a future therapeutic target or biomarker; no therapeutic agents directly targeting PREX2 are currently available PMID:22622578
  • PREX2 loss or mutation may modulate PI3K/AKT signaling via PTEN regulation, potentially informing sensitivity to PI3K pathway inhibitors

Open questions

  • The precise oncogenic mechanism of PREX2 mutations remains unclear; mutations are distributed across the gene (not confined to hotspots), and the paper notes they may act through dominant-negative effects or subtle dysregulation rather than classic gain-of-function or loss-of-function PMID:22622578
  • Functional validation was performed in NRAS-mutant melanocyte backgrounds only; relevance to BRAF-mutant or wild-type contexts is unexplored PMID:22622578

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:26551667

This page was processed by crosslinker on 2026-05-14. - PMID:28373299

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