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Updated: Jun 2, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
FBXW7 mutations typically found in human cancers are distinct from null alleles and disrupt lung development
Hayley Davis1, Annabelle Lewis, Bradley Spencer-Dene
1Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
Abstract:
FBXW7 is the substrate recognition component of a SCF-type E3 ubiquitin ligase. It has multiple targets such as Notch1, c-Jun, and cyclin E that function in critical developmental and signalling pathways. Mutations in FBXW7 are often found in many types of cancer. In most cases, these mutations do not inactivate the protein, but are mono-allelic missense changes at specific arginine resides involved in substrate binding. We have hypothesized that FBXW7 mutations are selected in cancers for reasons other than haploinsufficiency or full loss-of-function. Given that the existing mutant Fbxw7 mice carry null alleles, we created a mouse model carrying one of the commonly occurring point mutations (Fbxw7(R482Q)) in the WD40 substrate recognition domain of Fbxw7. Mice heterozygous for this mutation apparently developed normally in utero, died perinatally due to a defect in lung development, and in some cases showed cleft palate and eyelid fusion defects. By comparison, Fbxw7(+/-) mice were viable and developed normally. Fbxw7(-/-) animals died of vascular abnormalities at E10.5. We screened known FBXW7 targets for changes in the lungs of the Fbxw7(R482Q/+) mice and found Tgif1 and Klf5 to be up-regulated. Fbxw7(R482Q) alleles are not functionally equivalent to heterozygous or homozygous null alleles, and we propose that they are selected in tumourigenesis because they cause a selective or partial loss of FBXW7 function.
Insights
FBXW7 mutations, common in cancer, cause partial protein loss, leading to lung defects and developmental issues in mice. This suggests a selective advantage in tumorigenesis beyond full loss-of-function.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- FBXW7 is a key component of the SCF E3 ubiquitin ligase complex, regulating critical developmental and signaling pathways.
- Mutations in FBXW7 are frequently observed in various cancers, typically as missense changes affecting substrate binding.
- Existing mouse models with null alleles do not fully recapitulate the nuances of cancer-associated FBXW7 mutations.
Purpose of the Study:
- To investigate the functional consequences of a specific cancer-associated FBXW7 point mutation (R482Q) in a mouse model.
- To determine if this mutation confers a selective advantage in tumorigenesis distinct from haploinsufficiency or full loss-of-function.
Main Methods:
- Generated a mouse model harboring the Fbxw7(R482Q) point mutation.
- Compared the developmental phenotypes of Fbxw7(R482Q/+) mice with wild-type and Fbxw7(+/-) littermates.
- Analyzed known FBXW7 targets in the lungs of Fbxw7(R482Q/+) mice.
Main Results:
- Fbxw7(R482Q/+) mice exhibited perinatal lethality due to lung development defects, cleft palate, and eyelid fusion.
- In contrast, Fbxw7(+/-) mice were viable and developed normally, while Fbxw7(-/-) mice died early from vascular defects.
- Up-regulation of FBXW7 targets Tgif1 and Klf5 was observed in the lungs of Fbxw7(R482Q/+) mice.
Conclusions:
- The Fbxw7(R482Q) mutation results in a distinct phenotype compared to null alleles, indicating a selective or partial loss of FBXW7 function.
- These findings support the hypothesis that FBXW7 point mutations are selected in cancer due to a partial loss-of-function mechanism, rather than complete inactivation.
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