HRAS

Overview

HRAS encodes a GTPase in the RAS/MAPK signaling pathway. In radiation-associated angiosarcoma, HRAS harbors hotspot missense mutations in the Ras GTPase domain (e.g., A59T, Q61R/L) at significantly higher frequency than sporadic angiosarcoma.

Alterations observed in the corpus

  • Missense and in-frame insertion/deletion mutations in 14% of RT-ANGS vs 2% of sporadic AS; all hotspot mutations at the Ras GTPase domain (A59T, Q61R/L) PMID:37350195.
  • Co-occurs with MYC amplification, FLT4, CRKL, and KMT2D alterations in breast/chest wall RT-AS PMID:37350195.
  • RAS/PIK3CA pathway alterations (including HRAS, along with PIK3CA, NRAS, KRAS) found in 5/17 fusion-negative rhabdomyosarcoma (FN-RMS) patients in a study of 35 tumor pairs PMID:37730754.
  • Recurrently mutated in HNSCC across 74 tumor-normal pairs by whole-exome sequencing (Broad cohort) PMID:21798893
  • Recurrently mutated in HNSCC across 32 primary tumors by whole-exome sequencing (Johns Hopkins cohort) PMID:21798897
  • Somatic mutations detected in melanoma WES cohort (Broad, 121 tumors) PMID:22817889
  • Significantly mutated in COSMIC-restricted analysis of lung squamous cell carcinoma (178 tumors, TCGA) PMID:22960745
  • Activating mutations strongly co-occur with CASP8 mutations in oral squamous cell carcinoma (OSCC); part of the mitogenic signaling pathway altered in 63% of HNSCC tumors PMID:23619168
  • Mutation present in a subset of bladder cancer cell lines and primary tumors within the MAPK-pathway alteration set (35% combined) in high-grade urothelial carcinoma; HRAS-mutant cell lines showed reduced sensitivity to the AKT inhibitor MK-2206 PMID:23897969
  • Confirmed recurrent driver mutation in transitional cell carcinoma (BLCA) by whole-exome sequencing of 99 Chinese TCC tumors; one of 7 previously known bladder cancer driver genes validated in the cohort PMID:24121792
  • HRAS codon 12/13/61 oncogenic hotspot mutations detected in rhabdomyosarcoma (RMS), predominantly in fusion-negative (PFN) tumors (4.3% frequency); no RAS mutations observed in fusion-positive PAX (PFP) tumors PMID:24436047
  • HRAS identified as a significantly mutated gene (SMG) at ≤8% frequency in muscle-invasive bladder cancers in TCGA urothelial carcinoma comprehensive genomic characterization PMID:24476821
  • RTK/RAS/RAF pathway mutation identified in 1 case of LUAD (TCGA, n=230); part of the broader RTK/RAS/RAF pathway altered in the majority of LUAD cases PMID:25079552
  • Mutated in 20.5% of 39 aggressive cSCC tumors; the most obvious oncogene identified but currently undruggable; positively correlated with AJUBA co-mutation (kappa 0.423, p=0.008) and inversely correlated with TP53 (kappa -0.107, p=0.004) PMID:25303977
  • RAS codon 12/61 SSNVs (NRAS/HRAS/KRAS) found in 52/402 (12.9%) papillary thyroid tumors; characterize the follicular variant and drive the RL (RAS-like) phenotype with concurrent MAPK/PI3K signaling PMID:25417114
  • G13D activating mutation identified as an oncogenic event in cSCC (cutaneous squamous cell carcinoma) PMID:25589618
  • Activating mutations (4%) at GTPase residues 11-13 in HNSCC; defines an M-class oral-cavity subset with CASP8 co-mutation and wild-type TP53 PMID:25631445
  • Rare hot-spot mutations (G13D/G13S/Q61K×2) identified in cutaneous melanoma; mutually exclusive with NRAS and BRAF V600/K601 hot-spots; part of the RAS-mutant subtype of melanoma PMID:26091043
  • Activating mutations in 13.6% of high-grade UTUC vs 1.0% of high-grade UCB (p=0.001); largely mutually exclusive with FGFR3 and TP53; supports FGFR3/HRAS-driven low-grade-tumor-progression model of UTUC carcinogenesis PMID:26278805
  • Cited as prior lenti-HrasQ61L mammary intraductal model: produces ER-/metaplastic tumors in mice but ER+/PR+ ductal carcinoma in rats, providing historical evidence of species-specific lineage plasticity motivating CRISPR-based ER+ breast cancer modeling PMID:26437033
  • Q61R hotspot in 3/4 HRAS-mutant primary prostate cancers; paralogous to the canonical RAS Q61 oncogenic position; co-occurs with other non-canonical RAS-family activations (RAC1 Q61R, RRAS2 Q72L) PMID:26544944
  • HRAS mutations occur collectively with NRAS and KRAS in 28% of PDTC and 24% of ATC; RAS mutations are mutually exclusive with BRAF V600E and gene fusions; RAS-mutant PDTCs trend toward distant metastasis and are enriched for Turin histological criteria PMID:26878173
  • Significantly mutated in lung SqCC but not other cancer types (excluding HNSC, BLCA) in the TCGA pan-lung cohort PMID:27158780
  • Classical hotspot activating mutations at codons 12/61 observed in 3 breast cancer samples; did not meet Mut-driver criteria as a standalone breast-cancer driver event in a 2,433-sample targeted sequencing study PMID:27161491
  • HRAS mutated in salivary duct carcinoma (SDCA) and one HNSC patient (treated on farnesyl-transferase-inhibitor trial); G13V observed in a mucoepidermoid carcinoma (MUCC) treated similarly; recurrent in SDCA in a cohort of 151 advanced head and neck tumors profiled by MSK-IMPACT 410-gene panel PMID:27442865
  • HRAS recurrent somatic Q61 hotspot mutations activate MAPK signaling in pheochromocytoma/paraganglioma; enriched in the kinase signaling molecular subtype PMID:28162975.
  • Single patient with HRAS mutation in prospective lung adenocarcinoma cohort (860 patients, MSK-IMPACT); HRAS is in the RAS family alongside KRAS and NRAS which are more commonly mutated in LUAD PMID:28336552
  • Hotspot MAPK-pathway mutation observed in ~5% of prostate cancer patients across all disease states in the 451-patient MSK-IMPACT cohort; co-detected with BRAF, KRAS, and MAP2K1 hotspot mutations PMID:28825054
  • Recurrent somatic mutations identified in HPV(−) vulvar squamous cell carcinoma (9-tumor subset) by whole-exome sequencing; consistent with prior targeted-panel literature on HPV(−) vulvar SCC PMID:29422544

Cancer types (linked)

  • ANGS — HRAS hotspot mutations enriched in RT-AS (14%) vs sporadic AS (2%); implicated in both the stress-activated MAPK cascade and VEGF/VEGFR signaling pathways PMID:37350195.
  • CESC — HRAS is part of the RAS/PIK3CA pathway alteration landscape assessed in 177 cervical cancer patients at MSK; no specific HRAS frequency reported separately PMID:37643132.
  • RMS — HRAS is among RAS pathway drivers in FN-RMS (5/17 patients with RAS/PIK3CA pathway alterations) PMID:37730754.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • HRAS is part of both the stress-activated MAPK cascade and VEGF/VEGFR signaling pathways identified as potential molecular targets in RT-AS PMID:37350195.

Open questions

  • Whether RAS-directed therapies or downstream MEK/ERK inhibitors are effective in HRAS-mutant RT-AS is not addressed in the corpus PMID:37350195.
  • The functional significance of the specific HRAS hotspot variants (A59T, Q61R/L) in angiosarcoma biology has not been characterized PMID:37350195.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:21798893

This page was processed by crosslinker on 2026-05-14. - PMID:21798897

This page was processed by crosslinker on 2026-05-14. - PMID:22817889

This page was processed by crosslinker on 2026-05-14. - PMID:22960745

This page was processed by crosslinker on 2026-05-14. - PMID:23619168

This page was processed by crosslinker on 2026-05-14. - PMID:23897969

This page was processed by crosslinker on 2026-05-14. - PMID:24121792

This page was processed by crosslinker on 2026-05-14. - PMID:24436047

This page was processed by crosslinker on 2026-05-14. - PMID:24476821

This page was processed by crosslinker on 2026-05-14. - PMID:25079552

This page was processed by crosslinker on 2026-05-14. - PMID:25303977

This page was processed by crosslinker on 2026-05-14. - PMID:25417114

This page was processed by crosslinker on 2026-05-14. - PMID:25589618

This page was processed by crosslinker on 2026-05-14. - PMID:25631445

This page was processed by crosslinker on 2026-05-14. - PMID:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26278805

This page was processed by crosslinker on 2026-05-14. - PMID:26437033

This page was processed by crosslinker on 2026-05-14. - PMID:26544944

This page was processed by crosslinker on 2026-05-14. - PMID:26878173

This page was processed by entity-page-writer on 2026-05-15. - PMID:27158780

This page was processed by entity-page-writer on 2026-05-15. - PMID:27161491

This page was processed by entity-page-writer on 2026-05-15. - PMID:27442865

This page was processed by entity-page-writer on 2026-05-15. - PMID:28162975

This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:29422544

This page was processed by wiki-cli on 2026-05-15.