FBXW7

Overview

FBXW7 (F-Box And WD Repeat Domain Containing 7) encodes an E3 ubiquitin ligase substrate recognition subunit that targets multiple oncoproteins (MYC, NOTCH1, CCNE1, JUN, MCL1) for proteasomal degradation. Loss-of-function mutations in FBXW7 lead to accumulation of these oncoproteins and are recurrent across many cancer types, classifying FBXW7 as a pan-cancer tumor suppressor.

Alterations observed in the corpus

  • Subthreshold recurrent inactivating mutations in meningioma (q = 0.226); enriched in more aggressive molecular groups (MG3/MG4) PMID:34433969.
  • Altered in 13% of squamous cervical cancers (OncoKB-annotated) PMID:37643132.
  • Co-occurs with TP53 mutations in serous/carcinosarcoma endometrial carcinomas PMID:37651310.
  • SNV detected in ctDNA at relapse in a fusion-negative rhabdomyosarcoma (FN-RMS) patient PMID:37730754.
  • Recurrently mutated in HNSCC across 32 primary tumors by whole-exome sequencing (Johns Hopkins cohort) PMID:21798897
  • Somatic mutations detected in TCGA colorectal adenocarcinoma cohort (276 tumors) PMID:22810696
  • 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
  • Among 25 significantly mutated genes identified by InVEx/MutSig in 183 LUAD cases PMID:22980975
  • Significantly mutated in microsatellite-stable colorectal cancer (Genentech WES, 74 tumors) PMID:22895193
  • Identified as significantly mutated in CLL (Broad cohort, 160 tumors); truncating and missense mutations in the WD40 substrate-recognition domain PMID:23415222
  • Mutated in 82% of POLE-ultramutated endometrial tumors and 22% of copy-number-high tumors; mutually exclusive with FGFR2/ERBB2 amplification in WNT module analysis PMID:23636398
  • R465H mutation identified in adenoid cystic carcinoma (ACC); tumor suppressor that targets MYC and NOTCH1 for degradation PMID:23685749
  • FBXW7 identified as a novel recurrent driver in 7.4% of fusion-negative rhabdomyosarcoma (PFN) tumors, exclusively at WD40-domain arginine residues R387P, R441G, and R367P PMID:24436047
  • FBXW7 mutated in 10% of muscle-invasive bladder cancers in TCGA urothelial carcinoma comprehensive genomic characterization PMID:24476821
  • Frequent inactivating mutations leading to protein loss (33% in validation cohort) in ESCC; confirmed by IHC on TMA PMID:24686850
  • Recurrently mutated in non-hypermutated CRC; mutation status concordant between primary tumor and metastasis per matched-pair sequencing PMID:25164765
  • Mutated in 5/22 gynaecologic carcinosarcomas (23%), including the canonical R505C WD-repeat hotspot; loss-of-function may sensitize tumors to HDAC inhibitors (preclinical) PMID:25233892
  • Enriched among large-duct-type iCCA; co-occurs with TGFBR2 and MYC alterations in this molecular subtype. PMID:25526346
  • Classic CRC driver; FBXW7 mutation frequency individually higher in AA than Caucasian CRCs, consistent with prior reports PMID:25583493
  • Recurrent Arg505Gly/Leu substitutions (n=14) in HNSCC; falls in 4q31.3 significant deletion peak; targets cyclin E and NOTCH for degradation PMID:25631445
  • Non-passenger mutations in breast adenoid cystic carcinoma (AdCC); also recurrent in salivary gland AdCCs; some mutations were subclonal PMID:26095796
  • Truncating and WD-domain damaging mutations in 11% of desmoplastic melanoma tumors; loss-of-function burden candidate PMID:26343386
  • Recurrently mutated gene identified in the TCGA pan-lung cancer cohort (lung ADC/SqCC) PMID:27158780
  • FBXW7 loss-of-function mutations were identified alongside ERBB2 alterations and evaluated for their role in therapy resistance PMID:28445112
  • R465H hotspot missense mutation in 1/19 (5%) FISH-confirmed 1p/19q-codeleted oligodendroglioma cases; unknown therapeutic implication PMID:28472509
  • Mutated in 7.9% of clear cell endometrial carcinoma (CCEC) in the UCCC-NIH targeted sequencing study PMID:28485815
  • Mutations in FBXW7 associated with elevated structural variant (SV) burden (q < 0.1) in cholangiocarcinoma (CCA) across a 489-sample ICGC multi-platform cohort PMID:28667006
  • Recurrently altered candidate driver in medulloblastoma across subgroups, identified in the ICGC/MAGIC 491-tumor WGS cohort; listed among additional recurrent driver genes stratified across subgroups PMID:28726821
  • Enriched in early-stage vs metastatic CRC in MSK-IMPACT sequencing of 1,134 colorectal adenocarcinomas, suggesting a possible protective or non-metastatic-driver role PMID:29316426
  • Novel mutation finding in HPV(+) vulvar squamous cell carcinomas identified by WES of 15 Korean vulvar SCC cases; not previously reported in HPV(+) vulvar SCC PMID:29422544

Cancer types (linked)

Co-occurrence and mutual exclusivity

  • Co-occurs with TP53 mutations in serous endometrial carcinoma and carcinosarcoma PMID:37651310.

Therapeutic relevance

  • Not reported in the corpus.

Open questions

  • None flagged in the corpus.

Sources

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

This page was processed by crosslinker on 2026-05-14. - PMID:22810696

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:22980975

This page was processed by crosslinker on 2026-05-14. - PMID:22895193

This page was processed by crosslinker on 2026-05-14. - PMID:23415222

This page was processed by crosslinker on 2026-05-14. - PMID:23636398

This page was processed by crosslinker on 2026-05-14. - PMID:23685749

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:24686850

This page was processed by crosslinker on 2026-05-14. - PMID:25164765

This page was processed by crosslinker on 2026-05-14. - PMID:25233892

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14. - PMID:25583493

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

This page was processed by wiki-cli on 2026-05-14. - PMID:26095796

This page was processed by wiki-cli on 2026-05-14. - PMID:26343386

This page was processed by wiki-cli on 2026-05-14. - PMID:27158780

This page was processed by wiki-cli on 2026-05-14. - PMID:28445112

This page was processed by wiki-cli on 2026-05-14. - PMID:28472509

This page was processed by wiki-cli on 2026-05-15. - PMID:28485815

This page was processed by wiki-cli on 2026-05-15. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:28726821

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

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

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