NRAS

Overview

NRAS is a RAS-family GTPase frequently mutated across cancers. In the corpus it defines the indolent RAS-mutant subtype of mucinous appendiceal adenocarcinoma and appears as a subclonal driver in histiocytosis and germ cell tumors.

Alterations observed in the corpus

  • RAS mutations (KRAS/NRAS) in the absence of GNAS and TP53 alterations define the clinically indolent MAAP subtype (n=24) with the lowest mutational/chromosomal burden and best OS PMID:36493333.
  • NRAS A59_E76 mutation in one histiocytosis patient treated with a MEK inhibitor; mostly subclonal in female germ cell tumors PMID:36862133.
  • Recurrently mutated in anaplastic thyroid carcinoma (ATC); no frequency difference between PTC and ATC; mutually exclusive with BRAF V600E PMID:38412093.
  • RAS/PIK3CA pathway alterations (including NRAS) in 5/17 fusion-negative rhabdomyosarcoma (FN-RMS) patients PMID:37730754.
  • Oncogenic Q61K mutation in a neuroendocrine prostate cancer (NEPC) patient-derived xenograft; described as seldom implicated in prostate cancer PMID:38488813.
  • Recurrent co-mutation in BRAF fusion-positive colorectal cancers and other BRAF fusion contexts (via MAPK pathway co-activation) PMID:38922339.
  • Mutated in cervical cancers (frequency not separately specified from KRAS); enriched in certain cervical cancer histologic subtypes PMID:37643132.
  • In the MSK 2,336-patient PDAC cohort, other-MAPK-mutant tumors carry NRAS (and other RAS/RAF pathway) oncogenic alterations nearly exclusive to KRAS-WT tumors (7% of KRAS-mutant tumors have other MAPK-pathway alterations vs 60% of KRAS-WT, P = 1.6×10⁻⁴⁷). PMID:39753968
  • Rare amplification observed in 188 primary LUAD tumours (TSP cohort); MAPK pathway member. PMID:18948947
  • NRASG12D acquired clonally in CRC C106-resistant cells; NRASQ61K/R detected in patient ctDNA at resistance to KRASG12C + EGFR inhibition PMID:36355783
  • NRAS alterations assessed in gallbladder carcinoma (GBC) genomic landscape study PMID:36228155
  • Mutated in high-grade serous ovarian carcinoma (HGSOC) in TCGA integrated genomic analysis PMID:21720365
  • Recurrently mutated in myelodysplastic syndrome (MDS) identified in Tokyo cohort sequencing study alongside STAG2 PMID:21909114
  • NRAS mutation status was characterized across 947 cancer cell lines in the CCLE pharmacogenomic profiling study, enabling drug sensitivity correlations PMID:22460905
  • NRAS harbors somatic mutations in melanoma; identified in WGS of 25 tumors alongside recurrent PREX2 mutations PMID:22622578
  • Codon 61 mutations in 9% of non-hypermutated colorectal tumors; mutually exclusive with KRAS and BRAF in 276-tumor TCGA CRC cohort PMID:22810696
  • Q61L/R/K hotspot mutations in 22% of melanomas (121-tumor Broad WES cohort); mutually exclusive with BRAF (p=3e-14) PMID:22817889
  • Q61 and other activating mutations represent the second most frequent driver in melanoma (15-20%) in the 147-tumor Yale WES cohort PMID:22842228
  • Activating mutations in near haploid ALL as part of RTK/Ras pathway (70.6% of cases); one inherited p.Gly12Ser germline variant identified; St. Jude WGS/WES cohort of 44 hypodiploid ALL tumors PMID:23334668
  • Activating missense mutations in 0.83% (2/240) of high-risk neuroblastoma; significant in COSMIC-restricted analysis; Broad WES/WGS cohort PMID:23334666
  • Novel CLL driver candidate; mutations at highly conserved Ras GTPase sites; identified in Broad WES cohort of 160 CLL tumors PMID:23415222
  • Non-FLT3 activated signaling gene; part of the 59% signaling-pathway prevalence in 200 adult de novo AML cases; mutually exclusive of FLT3 and other tyrosine kinases within the signaling mutual-exclusivity set (TCGA AML cohort) PMID:23634996
  • Single hotspot mutation detected in IHCH discovery screen; additional NRAS hits in the prevalence screen confirm RAS signaling involvement in intrahepatic cholangiocarcinoma PMID:24185509
  • Acquired resistance mutations (Q61R/K/H, T58I, Q60H) in 17.8% of resistant BRAF V600-mutant melanoma tumors; acquisition restricted to patients with >12-week response duration (P = 0.04), suggesting a late resistance mechanism PMID:24265153
  • Recurrent MAPK-activating point mutations in multiple myeloma; frequently subclonal and occasionally co-mutated with BRAF (rarely simultaneously clonal) PMID:24434212
  • Codon 12/13/61 oncogenic hotspot mutations in rhabdomyosarcoma; predominantly in fusion-negative (PFN) tumors (frequency 6.4%); no RAS mutations observed in the fusion-positive PAX-FOXO1 (PFP) subset PMID:24436047
  • RAS mutations are rare in HCC (~1% each for KRAS and NRAS; only 4.4% of 1,318 ctDNA samples in BEAMing screening); a biomarker-enriched phase II of refametinib + sorafenib in 16 RAS-mutant patients reported median OS 12.7 months PMID:24798001
  • NRAS mutation (n=1) observed as an additional RTK/RAS/RAF pathway alteration in LUAD (TCGA, n=230) PMID:25079552
  • One activating somatic mutation in 66 chromophobe RCC cases; contributes to mTOR-pathway alteration rate of 23% combined with PTEN/MTOR/TSC1/TSC2 PMID:25155756
  • Driver mutations in KRAS/NRAS/BRAF are 100% concordant between primary and metastasis in CRC; trunk events established early in carcinogenesis; status guides cetuximab and panitumumab eligibility PMID:25164765
  • Hotspot mutations absent in 39-case aggressive cSCC cohort — explicit negative finding distinguishing cSCC from other squamous and melanocytic malignancies PMID:25303977
  • NRAS codon 12/61 SSNVs in 52/402 (12.9%) PTC tumors along with HRAS/KRAS; characterize the follicular variant and drive the RL phenotype; mutually exclusive with BRAFV600E PMID:25417114
  • NRAS mutation status used as a baseline driver-mutation stratifier in melanoma patients receiving CTLA-4 blockade (ipilimumab/tremelimumab); no significant enrichment by clinical benefit category was observed PMID:25409260
  • In cutaneous melanoma (SKCM), NRAS is mutated in 28% of cases; dominant hot-spots are Q61R (35), Q61K (28), Q61L (11), Q61H (4); defines the RAS genomic subtype. Mutations are mutually exclusive with BRAF V600/K601 hot-spots; NRAS amplifications co-occur with NRAS mutations. Highest phospho-ERK1/2 by RPPA in RAS subtype. PMID:26091043
  • Canonical Q61K/R mutations absent in desmoplastic melanoma; one tumor harbored atypical Q61H substitution. PMID:26343386
  • Mutated in n=9 cases as part of the 4.1% RAS-mutant CLL fraction in a 538-sample WES cohort; contributes to the 8.7% of CLLs with MAPK-pathway mutations for which MEK inhibition is proposed PMID:26466571
  • No enrichment of nonsynonymous NRAS mutations by clinical-benefit vs. no-benefit subgroups in a 110-patient metastatic melanoma cohort treated with ipilimumab (CTLA-4 blockade), despite prior reports linking NRAS status to immunotherapy response PMID:26359337
  • Ras-pathway oncogene recurrently mutated (n=5) in diffuse glioma; previously known mainly from engineered mouse models PMID:26824661
  • NRAS identified as a known CRC driver and source of recurrent neopeptides in 619-tumor whole-exome sequencing study (NHS/HPFS cohort) PMID:27149842
  • Late driver in RTK-RAS pathway in AML; G12/13 vs. Q61 hotspots have distinct co-mutation patterns; G12/13 in NPM1/DNMT3A context paradoxically favorable; G12/13 but not Q61 modifies DNMT3A-FLT3-ITD-NPM1 interaction PMID:27276561
  • 4 mutations in cisplatin-resistant germ cell tumors (GCT); 3 of 4 in cisplatin-resistant tumors; MEK inhibitors (trametinib, selumetinib, binimetinib) listed as targeted therapy candidates PMID:27646943
  • Ras-pathway activating mutations (including NRAS G12D) in 35.2% of DUX4/ERG B-ALL cases; NRAS G12D cooperated with dominant-negative ERGalt to sustain lymphoid colony replating in Arf−/− mouse cells PMID:27776115
  • Activating NRAS mutations (Q61H, Q61R, Q61K, G13A, G13D) across multiple pediatric AML, ALL, neuroblastoma (NBL), and rhabdomyosarcoma (RMS) cases; MEK-inhibitor targets identified in a pediatric precision-oncology cohort PMID:28007021
  • 10 mutations detected in a prospective LUAD cohort (860 patients): 9 Q61 and 1 G13; no patient with NRAS as highest-level driver received matched therapy PMID:28336552
  • 4 mutations in 34 acral melanoma (ALM) patients: Q61K in 3 (9%) and A59G in 1; mutually exclusive of BRAF mutations in this cohort PMID:28373299
  • OncoKB Level 1 resistance marker for anti-EGFR antibodies (cetuximab/panitumumab) in mCRC; HR=2.59 for OS in multivariate analysis of MSS metastatic CRC (N=1,152) PMID:29316426

Cancer types (linked)

  • Appendiceal adenocarcinoma (APAD) — defines indolent RAS-mut predominant MAAP subtype PMID:36493333.
  • Histiocytosis (LCH, ECD) — rare activating mutation PMID:36862133.
  • Anaplastic thyroid carcinoma (ATC) — recurrent, frequency equivalent in PTC and ATC; mutually exclusive with BRAF V600E PMID:38412093.
  • Rhabdomyosarcoma (FN-RMS) — RAS pathway activating alterations in 5/17 patients PMID:37730754.
  • Prostate cancer (NEPC) — rare NRAS Q61K mutation in patient-derived xenograft model PMID:38488813.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • RAS-mut predominant MAAP showed 50% first-line chemotherapy response rate vs 6% in GNAS-mut predominant PMID:36493333.
  • NRAS-mutant histiocytosis responded to MEK inhibition PMID:36862133.

Open questions

  • Whether RAS-mut MAAP patients should receive less aggressive management, given small subtype N and no cancer-specific deaths PMID:36493333.

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:18948947

This page was processed by entity-page-writer on 2026-05-15. - PMID:36355783

This page was processed by entity-page-writer on 2026-05-15. - PMID:36228155

This page was processed by entity-page-writer on 2026-05-15. - PMID:21720365

This page was processed by entity-page-writer on 2026-05-15. - PMID:21909114

This page was processed by entity-page-writer on 2026-05-15. - PMID:22460905

This page was processed by entity-page-writer on 2026-05-15. - PMID:22622578

This page was processed by entity-page-writer on 2026-05-15. - PMID:22810696

This page was processed by entity-page-writer on 2026-05-15. - PMID:22817889

This page was processed by entity-page-writer on 2026-05-15. - PMID:22842228

This page was processed by entity-page-writer on 2026-05-15. - PMID:23334668

This page was processed by entity-page-writer on 2026-05-15. - PMID:23334666

This page was processed by entity-page-writer on 2026-05-15. - PMID:23415222

This page was processed by entity-page-writer on 2026-05-15. - PMID:23634996

This page was processed by entity-page-writer on 2026-05-15. - PMID:24185509

This page was processed by entity-page-writer on 2026-05-15. - PMID:24265153

This page was processed by entity-page-writer on 2026-05-15. - PMID:24434212

This page was processed by entity-page-writer on 2026-05-15. - PMID:24436047

This page was processed by entity-page-writer on 2026-05-15. - PMID:24798001

This page was processed by entity-page-writer on 2026-05-15. - PMID:25079552

This page was processed by entity-page-writer on 2026-05-15. - PMID:25155756

This page was processed by entity-page-writer on 2026-05-15. - PMID:25164765

This page was processed by entity-page-writer on 2026-05-15. - PMID:25303977

This page was processed by entity-page-writer on 2026-05-15. - PMID:25417114

This page was processed by entity-page-writer on 2026-05-15. - PMID:25409260

This page was processed by entity-page-writer on 2026-05-15. - PMID:26091043

This page was processed by entity-page-writer on 2026-05-15. - PMID:26343386

This page was processed by entity-page-writer on 2026-05-15. - PMID:26466571

This page was processed by entity-page-writer on 2026-05-15. - PMID:26359337

This page was processed by entity-page-writer on 2026-05-15. - PMID:26824661

This page was processed by entity-page-writer on 2026-05-15. - PMID:27149842

This page was processed by entity-page-writer on 2026-05-15. - PMID:27276561

This page was processed by entity-page-writer on 2026-05-15. - PMID:27646943

This page was processed by entity-page-writer on 2026-05-15. - PMID:27776115

This page was processed by entity-page-writer on 2026-05-15. - PMID:28007021

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

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