FBXW7 loss-of-function mutation

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`BIO-FBXW7`
Type	Biomarker
Aliases	FBXW7 mutationМутація втрати функції FBXW7
Status	reviewed 2026-05-04 \| pending_clinical_signoff
Diseases	None declared
Sources	`SRC-ESMO-CRC-2024` `SRC-NCCN-COLON-2025`

Biomarker Facts

Biomarker type	gene_mutation
Mutation details	{"exon": "multiple; hotspot arginine triad R465, R479, R505 in WD40 substrate-recognition domain", "functional_impact": "loss-of-function (impaired ubiquitin-mediated degradation of oncoproteins: NOTCH1/2, MYC, CCNE1, mTOR, JUN, MCL-1)", "gene": "FBXW7", "variant_type": "loss-of-function (missense at Arg triad, frameshift, nonsense)"}
Measurement	MethodTumor NGS panel (DNA); RNA-seq for expression loss (research)
Actionability lookup	{"gene": "FBXW7", "variant": "loss_of_function"}
Related biomarkers	`BIO-NOTCH1` `BIO-KRAS` `BIO-TP53` `BIO-CDKN2A`

Notes

FBXW7 (F-Box and WD Repeat Domain Containing 7) is the substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex. FBXW7 recognizes phosphodegrons on multiple oncoproteins and mediates their ubiquitin-proteasomal degradation. Key substrates: NOTCH1/2, MYC, CCNE1, mTOR, JUN, MCL-1. Loss of FBXW7 → stabilization of these oncoproteins → resistance to multiple targeted therapies. Frequency: ~10–15% CRC (one of highest across cancers), ~15% T-ALL, ~6% gastric, ~5% pancreatic. Clinical significance: FBXW7 mutation is a resistance mechanism (to anti-NOTCH, CDK4/6i via CCNE1 upregulation, mTOR inhibitors via mTOR stabilization) rather than an independent therapeutic target. In CRC, FBXW7 mutation does not select any approved systemic therapy; it may co-occur with MSI-H (favoring immunotherapy) but is not independently actionable. ESCAT IV.

Used By

Actionability

BMA-FBXW7-CRC - FBXW7 loss-of-function mutations occur in ~10–15% of CRC and result in stabilization of m...