NF1

Overview

NF1 encodes neurofibromin, a RAS GAP tumor suppressor. Loss activates RAS signaling and is recurrent across diverse cancer types including lung adenocarcinoma, MPNST, anaplastic thyroid carcinoma, rhabdomyosarcoma, endometrial carcinoma, melanoma, and hepatocellular carcinoma.

Alterations observed in the corpus

  • Somatic mutations and deletions identified in 18% of GBM cases, establishing it as a major tumor suppressor in glioblastoma PMID:18772890.
  • LUAD: NF1 alterations associated with worse metastasis-free survival (p<0.001) in the MSK organotropism cohort (n=2,532) PMID:37084736.
  • NSCLC brain metastases: NF1 alterations more frequent in LMD patients (15%) than other progression groups PMID:37591896.
  • NF1 inactivating mutations/deletions in 67% of RT-MPNST vs 36% of sporadic MPNST (n=12 RT-MPNST, n=64 sporadic MPNST); one of the most enriched alterations in radiation-associated MPNST PMID:37350195.
  • Focal CNA loss on chromosome 17 in anaplastic thyroid carcinoma (ATC); identified among recurrent copy-number alterations PMID:38412093.
  • Driver events (with FGFR1) in a subset of fusion-negative rhabdomyosarcoma (FN-RMS) PMID:37730754.
  • Somatic mutations more frequent in carcinosarcomas from Black endometrial cancer patients (12% vs. 1% in White patients) PMID:37651310.
  • Multiple loss-of-function mutations (Q1595, V2511fs, R416, R2517, Q282, R1241*, splice-site, E1034K) in melanocytes; most frequently mutated gene across tanning and control cohorts in indoor tanning melanoma study PMID:38895302.
  • NF1 alterations (4%) detected in cell-free DNA from advanced hepatocellular carcinoma patients via cfDNA profiling PMID:37769223.
  • Plasma ctDNA NF1 alterations associated with cancer-associated venous thromboembolism risk PMID:39147831.
  • NF1 enriched after prior therapy in BRCA, confirming the endocrine-resistance signature alongside ESR1 and CCND1, in the MSK-CHORD pan-cancer cohort (n=52,211 patients). PMID:39506116
  • Not specifically tabulated as a recurrent driver in the MSK 2,336-patient PDAC cohort, but MAPK-pathway context relevant as NF1 is a RAS-GTPase activating protein. PMID:39753968
  • NF1 was mutated (point mutations + genomic deletions) in 10.5% of myxofibrosarcomas (MFS) and 8% of pleomorphic liposarcomas (PLLS) across 207 high-grade soft tissue sarcomas (sarc_mskcc); biallelic inactivation was observed in some tumors; NF1 loss linked to mTOR pathway activation, providing rationale for mTOR inhibitor therapy in these subtypes; first report of somatic NF1 alterations outside MPNST/GIST in NF1 patients PMID:20601955.
  • 16 mutations in 13 patients (4 nonsense, 5 splice-site, 1 frameshift) in LUAD; homozygous deletion in one tumour; newly implicated as a LUAD driver gene; mutations suggest MEK inhibitor sensitivity. PMID:18948947
  • Germline P/LP variants in 7/35 (20%) KIT/PDGFRA-wildtype GIST patients; 86% had NF1 clinical features PMID:36593350
  • Mutated in 10% of a longitudinal African breast cancer cohort PMID:36585450
  • Biallelic loss via chromoplexy in a myoepithelial carcinoma (MEC1) PMID:36577525
  • NF1 mutations (T676P, R2637*) detected in CRC patient ctDNA at resistance to KRASG12C + EGFR inhibition PMID:36355783
  • Mutated in high-grade serous ovarian carcinoma (HGSOC) in TCGA integrated genomic analysis PMID:21720365
  • Driver mutations identified in breast cancer WES (100 tumors, Sanger cohort); NF1 classified among known cancer gene drivers from other tumour types observed in breast cancer PMID:22722201
  • Loss-of-function mutations in 25% of BRAF/NRAS wild-type melanomas vs 2% of BRAF/NRAS-mutant (p=5.8e-3); identified by InVEx as significantly mutated gene in 121-tumor Broad WES cohort PMID:22817889
  • Inactivating mutations in 30% of BRAF/NRAS wild-type sun-exposed melanomas in 147-tumor Yale WES cohort PMID:22842228
  • NF1 mutation, deletion, and rearrangement identified in lung squamous cell carcinoma (TCGA, 178 tumors); associated with basal subtype PMID:22960745
  • NF1 inactivating mutations in 11% of lung adenocarcinoma tumors (Broad WES, 183 tumors); co-occurred with U2AF1 mutations (P = 0.0011) PMID:22980975
  • Novel significantly mutated gene in breast cancer (TCGA, 510 tumors); identified among novel SMGs PMID:23000897
  • Focal intragenic deletions (exons 15-35) and sequence mutations in 44.1% of near haploid ALL; biallelic loss in 76.7% due to aneuploidy; novel intragenic deletion via aberrant RAG activity causes loss of GAP domain and NF1 protein expression (St. Jude, 44 tumors) PMID:23334668
  • Mutated in 2% (3/145) of esophageal adenocarcinomas; MAPK-pathway mutations are uncommon in EAC, contrasting with colorectal cancer where BRAF mutations are frequent PMID:23525077
  • Germline + somatic second hit observed in 3 NF1-associated pilocytic astrocytoma cases; somatic NF1 alterations also co-occurred with FGFR1 and H3-3A K27M mutations in pediatric glioblastoma PMID:23817572
  • Somatic mutation in ~2% of high-grade urothelial bladder tumors; part of the RTK–RAS–RAF pathway alteration set (35% combined) PMID:23897969
  • Deletion/mutation in 10% of GBM; enriched in mesenchymal subtype; never co-occurring with BRAF V600E mutation; associated with elevated p-ERK/p-MEK by RPPA PMID:24120142
  • Included among MAPK-pathway resistance genes in BRAF V600-mutant melanoma; contributes to the 44.4% aggregate MAPK-pathway resistance gene rate observed in treated patients PMID:24265153
  • Single frameshift mutation identified in the sinonasal adenoid cystic carcinoma cohort; observed as a minor single-case hit PMID:24418857
  • Mutated in 5.3% of fusion-negative rhabdomyosarcoma (PFN) plus 9% with 17q11.2 LOH; functions as a RAS-axis tumor suppressor in RMS pathogenesis PMID:24436047
  • NF1 added to the significantly mutated gene list in MSI gastric tumors after inclusion of indels PMID:25079317
  • NF1 loss-of-function mutations in 11% of LUAD (TCGA, n=230); enriched in oncogene-negative subset; co-mutated with TP53 in PI subtype; nominated as driver by MutSig2CV PMID:25079552
  • Nonsense mutations and homozygous deletion in 82% of sporadic/radiotherapy-associated MPNSTs; significantly co-occurs with PRC2 loss (EED/SUZ12) and CDKN2A loss PMID:25240281
  • NF1 among tumor suppressor genes mutated in 15/402 (3.7%) PTC tumors; candidate dark-matter driver in papillary thyroid carcinoma PMID:25417114
  • NF1 inactivating events in 1–3 metastatic cSCC samples as a negative regulator of the RAS/RTK/PI3K pathway. PMID:25589618
  • NF1 alteration in 3% of HPV(−) HNSC (TCGA, n=279). PMID:25631445
  • In cutaneous melanoma (SKCM), NF1 is mutated in 14% of cases (>50% loss-of-function: 27 nonsense, 9 splice, 4 frameshift); defines the NF1 genomic subtype with highest mutation prevalence (~39 mut/Mb); ~70% of non-hot-spot BRAF/NRAS UV-signature tumors carry NF1 mutations. Anti-correlated with hot-spot BRAF (p=1.93e–9). PMID:26091043
  • Loss-of-function mutations and focal deletions in 4 desmoplastic melanoma cases; RAS pathway tumor suppressor lost in a BRAF/NRAS-wild-type melanoma context PMID:26343386
  • Indel editing of rat Nf1 alone produced ER+/PR+/Ki67+ ductal carcinoma in situ at 4-week median latency (12/13 cases, ~80% allelic editing); NF1 acts as a RAS GAP and ER-alpha transcriptional co-repressor; 4% somatic mutation and 20% copy-number loss rates in early ER+ human breast cancer; Nf1-loss tumors are highly endocrine-sensitive and regress on ovariectomy/fulvestrant PMID:26437033
  • MAPK-pathway alteration enriched in PA-like LGG (52%) and LGm6-GBM (32%) subtypes in the TCGA/CGGA diffuse glioma cohort PMID:26824661
  • NF1 truncating mutations in 3 BRAF/RAS-WT ATCs; all co-occurred with PTEN truncation (P = 2×10⁻³), suggesting NF1-PTEN co-inactivation as an alternative oncogenic axis in BRAF/RAS-wild-type anaplastic thyroid carcinoma PMID:26878173
  • NF1 somatic alterations observed in pan-lung cancer TCGA analysis (n=1144) across lung adenocarcinoma and squamous cell carcinoma subtypes PMID:27158780
  • NF1 inactivating mutations associated with shorter breast cancer-specific survival in ER- tumours (HR=2.7) in 2,433-tumor whole-genome/exome sequencing study PMID:27161491
  • Interesting structural variant identified in salivary duct carcinoma (SDCA) PMID:27442865
  • Germline (3%) and somatic NF1 mutations in pheochromocytoma/paraganglioma; 17q11.2 focal deletion present in 95% of NF1-mutated tumors; an NF1–RAB11FIP4 underexpressed fusion was also identified PMID:28162975
  • Truncating mutations and deletions in 16 LUAD patients (level 4); enriched in TCGA LUAD cohort vs MSK clinical cohort (8.3% vs 2%, p<0.001) PMID:28336552
  • Homozygous loss in 9% (3/34) of acral melanoma patients; additionally LOH plus nonsense mutation E2578* in one further patient; NF1-subtype tumors were BRAF/NRAS wild-type with co-occurring PAK1 copy gains PMID:28373299
  • Mutated in 4/19 (21%; F1247Ifs18, F1455Lfs9, F2386, K2595Sfs*5) in 1p/19q-codeleted anaplastic oligodendroglioma; also found in 1p/19q-intact glioblastoma-like tumors; none of the individual mutations were predictive of PFS or OS in this small NGS subset PMID:28472509
  • Most commonly fused tumor suppressor in MET500 500-patient metastatic cancer cohort (n=18 fusion events) PMID:28783718
  • Mutations in NF1 were associated with more favorable overall survival in DLBCL (combined GCB and ABC cohort analysis of 1001 patients) PMID:28985567
  • Homozygous copy-number deletions in NF1 were manually reviewed and confirmed in melanoma patients treated with nivolumab as part of copy-number analysis from the Riaz et al. cohort PMID:29033130
  • Truncating mutations in NF1 (n=3) were found among potentially functional driver mutations in the TCGA sarcoma cohort; NF1 shallow deletions occurred in 22% and deep deletions in 6% of DDLPS; NF1 was not epigenetically silenced in bladder cancer (no promoter hypermethylation detected) PMID:29100075
  • Two LP/PVs (one pLoF, one truncating intronic splice-region variant) in German pediatric cancer predisposition cohort; burden OR=9.8, p=.020 single-cohort, confirmed in joint analysis; one carrier (LPP_20) co-carried CHEK2 LP/PV and lacked typical NF1 clinical features; no CNV analysis performed so carrier frequency may be underestimated. PMID:29489754

Cancer types (linked)

  • GBM — inactivated through both homozygous deletions and somatic mutations in 18% of cases PMID:18772890.
  • LUAD — worse MFS in NF1-altered primaries PMID:37084736.
  • NSCLC — enriched in leptomeningeal disease after NSCLC brain metastasis PMID:37591896.
  • MPNST — NF1 inactivation enriched in RT-MPNST (67%) vs sporadic MPNST (36%) PMID:37350195.
  • Anaplastic thyroid carcinoma (ATC) — focal CNA loss on chromosome 17 PMID:38412093.
  • Rhabdomyosarcoma (FN-RMS) — driver event in a subset, co-occurring with FGFR1 alterations PMID:37730754.
  • Endometrial carcinoma carcinosarcoma — enriched in Black patients (12% vs. 1% in White patients) PMID:37651310.
  • Melanoma — most frequently mutated gene with multiple distinct LoF mutations in normal melanocytes from indoor tanning cohort PMID:38895302.
  • Hepatocellular carcinoma (HCC) — detected in 4% of cfDNA samples PMID:37769223.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • NF1 loss activates RAS/MAPK signaling; MEK inhibitors rationale applies but no specific trial data reported in this corpus for ATC or RMS.
  • NF1 mutations in carcinosarcomas from Black EC patients highlight a therapeutic gap where fewer actionable alterations overlap with current trial designs PMID:37651310.

Open questions

  • Whether NF1 loss functionally drives leptomeningeal tropism or is a marker of aggressive disease is not resolved PMID:37591896.
  • Whether NF1 loss in FN-RMS represents a genuine driver vs. passenger event requires functional studies.

Sources

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