RHOA

Overview

RHOA encodes a small GTPase of the Rho family that regulates actin cytoskeleton organization, cell cycle progression, and gene expression. RHOA hotspot mutations are recurrent oncogenic drivers in diffuse-type gastric adenocarcinoma (DSTAD), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma (ATLL), and other peripheral T-cell lymphomas (PTCL). Mutations are functionally heterogeneous – some are gain-of-function (GOF) and others are loss-of-function (LOF) – engaging distinct cellular programs.

Alterations observed in the corpus

  • Somatic RHOA hotspot mutations in ~25% of diffuse-type gastric cancers (22/87; Kakiuchi et al. 2014, cited). PMID:24816255
  • Germline RHOA p.R129W variant segregated in one Korean HDGC-like family with elevated GTP-binding and perturbed YAP1 signaling in functional assays. PMID:24816255
  • R5Q – attenuated-output LOF; recurrent in DSTAD and Burkitt lymphoma (BL); complements RHO1 in yeast and clusters morphologically near wild-type. PMID:24816253
  • G17V – dominant-negative LOF; abolishes GTP binding; present in ~67% of AITL cases and other PTCL; complements RHO1 in yeast but clusters morphologically with GOF mutants. PMID:24816253
  • C16R – GOF (accelerates GTP/GDP cycling); predominantly in ATLL; complements RHO1 in yeast. PMID:24816253
  • A161P – GOF; predominantly in ATLL; uniquely shows reproducible Slt2 (MAPK) phosphorylation elevation in yeast and the greatest number of altered CalMorph features (164 significantly altered parameters, FDR<0.05). PMID:24816253
  • E40Q – fails to complement RHO1 in yeast (no viable colonies on 5-FOA); recurs in solid tumors including breast cancer and HNSC. PMID:24816253
  • Mutated in 15% of genomically stable (GS) gastric tumours; novel hotspots in the effector-binding region (Y42, D59 etc.) distinct from RAS-family oncogenic sites; mutually exclusive with CLDN18-ARHGAP fusions. PMID:25079317
  • RHOA enriched in diffuse-type gastric cancer (GC), consistent with prior reports; not associated with shorter survival in the Tianjin Chinese GC cohort (n=294), distinguishing its clinical impact from CDH1-driven diffuse GC. PMID:25583476
  • Two distinct somatic mutations in 2/25 ACC tumors; first reported occurrence in ACC (RHOA hotspot mutations were previously known in angioimmunoblastic T-cell lymphoma) PMID:26862087
  • RHOA is a CRISPR-essential dependency in DLBCL associated with proliferation gene-expression signatures PMID:28985567

Cancer types (linked)

Co-occurrence and mutual exclusivity

  • Germline RHOA p.R129W co-occurs with altered YAP1 signaling in a Korean HDGC-like family. PMID:24816255

Therapeutic relevance

  • Rho/ROCK or YAP1-pathway inhibitors hypothesized as susceptible targets for RHOA-activated diffuse GC tumors (preclinical hypothesis; no clinical validation). PMID:24816255
  • All four viable RHOA mutant alleles (R5Q, G17V, C16R, A161P) confer myriocin resistance in yeast, pointing to TORC2 as a common downstream node potentially exploitable across mutation classes. PMID:24816253
  • CalMorph morphological profiling in yeast separates GOF (C16R, A161P) from LOF (R5Q, G17V) mutants by linear discriminant analysis, demonstrating distinct cellular programs that could inform class-specific therapeutic strategies. PMID:24816253

Open questions

  • Functional divergence between GOF and LOF RHOA mutations suggests different therapeutic vulnerabilities, but cross-allele comparison in mammalian systems has not been performed. PMID:24816253
  • Candidate germline RHOA variants in FNHGC await external validation in large independent cohorts. PMID:24816255

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:25079317

This page was processed by crosslinker on 2026-05-14. - PMID:25583476

This page was processed by crosslinker on 2026-05-14. - PMID:26862087

This page was processed by wiki-cli on 2026-05-14. - PMID:28985567

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