NF2

Overview

NF2 encodes merlin, a FERM-domain tumor suppressor that regulates Hippo signaling and contact inhibition. Biallelic NF2 inactivation (point mutations plus chromosome 22q loss) is the most common driver of meningioma (MG1 molecular group) and is enriched in biphasic diffuse pleural mesothelioma. Germline NF2 mutations cause neurofibromatosis type 2.

Alterations observed in the corpus

  • Point mutations plus chromosome 22q loss causing biallelic inactivation; near-universal in MG1 meningioma molecular group (88%); rare in MG2 (9%); some NF2-wildtype MG3/MG4 showed expression silencing without methylation changes in an integrative molecular study of 983 meningiomas PMID:34433969.
  • Altered in 90% of genomic near-haploidization (GNH) diffuse pleural mesotheliomas (DPMs), but this association is confounded by biphasic histology enrichment in the GNH subset PMID:38630790.
  • Recurrently mutated in clear cell renal cell carcinoma (ccRCC) identified by TCGA KIRC molecular subtyping study PMID:22138691
  • Newly nominated significantly mutated gene in papillary renal cell carcinoma (pRCC) PMID:25401301
  • NF2 within the 22q loss region characteristic of the SCNA-22q-del follicular-variant PTC subtype; also among tumor suppressors mutated in 15/402 (3.7%) PTC tumors PMID:25417114
  • NF2 inactivating events observed in metastatic cSCC (n=29) as a chromatin/tumor suppressor hit. PMID:25589618
  • NF2 infrequent truncating mutations observed in PDTC and ATC as part of a set of low-frequency tumor-suppressor alterations PMID:26878173
  • NF2 is focally deleted by the only chromosome-22 deletions that spare SMARCB1 in extra-cranial malignant rhabdoid tumor (MRT), along with LIF; observed in a minority of the 40 WGS MRT cases PMID:26977886
  • Recurrent truncating and missense mutations in 18% of unclassified RCC (uRCC); biallelic inactivation via mutation plus 22q12 LOH defines the dominant NF2-loss uRCC subset; drives Hippo–YAP dysregulation and confers significantly worse cancer-specific and progression-free survival PMID:27713405
  • A truncating mutation in NF2 (n=1) was identified among potentially functional driver mutations surveyed in the TCGA sarcoma cohort PMID:29100075

Cancer types (linked)

  • Meningioma (MG1 molecular group) — near-universal NF2 biallelic inactivation defines the MG1 (benign, low-recurrence) meningioma subgroup; NF2-wildtype defines MG2 (with TRAF7/AKT1/KLF4/SMO mutations) PMID:34433969.
  • Diffuse pleural mesothelioma (GNH subset) — enriched in biphasic DPMs with genome-wide near-haploidization; confounded by histology PMID:38630790.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • MG2 meningiomas (NF2-wildtype) harboring TRAF7/AKT1/KLF4/SMO mutations may be amenable to targeted therapies; MG1 (NF2-mutant) tumors currently lack effective medical therapies PMID:34433969.

Open questions

  • The mechanism of NF2 expression silencing in NF2-wildtype MG3/MG4 meningiomas (without methylation changes) is not characterized.
  • Whether NF2 alteration in GNH DPMs is a driver or a consequence of genome-wide LOH requires functional studies.

Sources

This page was processed by crosslinker on 2026-04-11. - PMID:22138691

This page was processed by wiki-cli on 2026-05-06. - PMID:25401301

This page was processed by wiki-cli on 2026-05-12. - PMID:25417114

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

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

This page was processed by wiki-cli on 2026-05-14. - PMID:26977886

This page was processed by wiki-cli on 2026-05-14. - PMID:27713405

This page was processed by entity-page-writer on 2026-05-15. - PMID:29100075

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