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FBXW7
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Interpretation 2301
Tier 2
FBXW7
Variants
FBXW7 R465H
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes and is inactivated by mutation in various cancers, most frequently in endometrial and colorectal cancers. Substrates of FBXW7 include the proteins c-MYC, mTOR, NOTCH1, cyclin-E, and JUN, which are instrumental in the regulation of cell division, differentiation and growth, and which are often inappropriately activated in cancer. Inactivation of FBXW7 by mutation or copy number loss results in aberrant accumulation of the above oncoproteins, which subsequently contributes to malignant transformation. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. Most mutations in FBXW7 are point mutations that disrupt substrate binding, while <10% are small deletions or insertions. FBXW7 is altered in 17% of colorectal adenocarcinomas. The FBXW7 R465H variant is considered to be likely oncogenic. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin. A single study has reported only limited activity in phase I trials using mTOR inhibitors in patients with advanced cancers including colorectal cancer. The clinical utility remains unknown.

Citations
  1. Comprehensive molecular characterization of human colon and rectal cancer. Cancer
  2. Genome Atlas Network 2012 Nature; 487(7407):330-7
  3. Jardim et al 2014. FBXW7 Mutations in Patients with Advanced Cancers: Clinical and
  4. Molecular Characteristics and Outcomes with mTOR Inhibitors. PLoS ONE 9(2).
  5. Mao JH, Kim IJ, Wu D, Climent J, Kang HC, DelRosario R, Balmain A. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science. 2008 Sep 12;321(5895):1499-502.
  6. Tong J, Tan S, Zou F, Yu J, Zhang L. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene. 2017 Feb 9;36(6):787-796. doi: 10.1038/onc.2016.247. Epub 2016 Jul 11.
  7. Wang Y, Liu Y, Lu J, Zhang P, Wang Y, et al. (2013) Rapamycin inhibits FBXW7 loss-
  8. induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in
  9. colorectal cancer cells. Biochem Biophys Res Commun.
  10. Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008 Feb;8(2):83-93. Review.
  11. Comprehensive TCGA PanCanAtlas (https://gdc.cancer.gov/about data/publications/pancanatlas)
Last updated: 2019-01-22 18:39:36 UTC
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