The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of f6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational ''hotspots,'' which alter Arg residues (Arg 465 and Arg 479 ) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.

This is the first comprehensive genetic screening and analysis of MTC among Iranian families. The results further confirm the need and advantages of DNA sequencing for identification of hereditary MTC cases. There does not seem to be a meaningful correlation between single nucleotide polymorphism patterns and the average age of disease onset. Geographical distribution of the sporadic cases, however, shows a significant concentration toward the Northern regions of the country, noticeably the provinces situated directly to the south of the Caspian Sea.

Conventional immunohistochemistry was unable to reveal any association between EGFR or HER-2 expression and outcome predicted by the biologic role of EGFR in tumor behavior and the established prognostic role of HER-2 in breast cancer.

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<div>Abstract<p>The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of <i>FBXW7</i> cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of <i>FBXW7</i> as a tumor suppressor in human tumorigenesis. Our results indicate that <i>FBXW7</i> is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational “hotspots,” which alter Arg residues (Arg⁴⁶⁵ and Arg⁴⁷⁹) that are critical for substrate recognition. Furthermore, we show that Fbxw7^Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of <i>FBXW7</i> mutations in various human malignancies and shows that <i>FBXW7</i> is a general tumor suppressor in human cancer. [Cancer Res 2007;67(19):9006–12]</p></div>