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Published on: February 5, 2018
Loss of CDC4/FBXW7 in gastric carcinoma
A N Milne1, R Leguit, W E Corver
1Department of Pathology, University Medical Centre, Utrecht, The Netherlands. a.n.a.milne@umcutrecht.nl
Background:
CDC4/FBXW7, encoding a ubiquitin ligase, maps to 4q32 and has been implicated as a tumor suppressor gene and therapeutic target in many tumor types. Mutations in colonic adenomas, and the frequent losses on 4q described in gastric cancer prompt speculation about the role of CDC4/FBXW7 in gastric carcinogenesis.
Methods:
We assessed the role of CDC4/FBXW7 in gastric cancer, through loss of heterozygosity (LOH) and multiplex ligation-dependent probe amplification (MLPA) on 47 flow-sorted gastric carcinomas including early-onset gastric cancers (EOGC) and xenografted conventional gastric carcinomas. Ploidy analysis was carried out on 39 EOGCs and immunohistochemistry of CDC4/FBXW7 and its substrates c-myc, c-jun, Notch and cyclin E was performed on 204 gastric carcinomas using tissue microarrays (TMAs). Sequence analysis of CDC4/FBXW7 was carried out on gastric carcinoma cell lines and xenografts.
Results:
Loss of heterozygosity of CDC4/FBXW7 occurred in 32% of EOGCs, and correlated with loss of expression in 26%. Loss of expression was frequent in both EOGC and conventional gastric cancers. No CDC4/FBXW7 mutations were found and loss of CDC4/FBXW7 did not correlate with ploidy status. There was a significant correlation between loss of CDC4/FBXW7 expression and upregulation of c-myc.
Conclusion:
Loss of CDC4/FBXW7 appears to play a role in both EOGC and conventional gastric carcinogenesis, and c-myc overexpression is likely to be an important oncogenic consequence of CDC4/FBXW7 loss.
Insights
Loss of CDC4/FBXW7, a tumor suppressor, is frequent in gastric cancers, including early-onset forms. This loss correlates with c-myc overexpression, suggesting a role in gastric carcinogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- CDC4/FBXW7 encodes a ubiquitin ligase implicated as a tumor suppressor and therapeutic target.
- Frequent losses on chromosome 4q in gastric cancer suggest a role for CDC4/FBXW7 in gastric carcinogenesis.
Purpose of the Study:
- To investigate the role of CDC4/FBXW7 in gastric carcinogenesis.
- To assess the frequency and consequences of CDC4/FBXW7 alterations in gastric cancers, including early-onset gastric cancers (EOGC).
Main Methods:
- Loss of heterozygosity (LOH) and multiplex ligation-dependent probe amplification (MLPA) were used to analyze 47 gastric carcinomas.
- Immunohistochemistry of CDC4/FBXW7 and its substrates (c-myc, c-jun, Notch, cyclin E) was performed on 204 gastric carcinomas.
- Sequence analysis of CDC4/FBXW7 was conducted on cell lines and xenografts.
Main Results:
- Loss of heterozygosity of CDC4/FBXW7 occurred in 32% of EOGCs, correlating with loss of expression in 26%.
- Loss of CDC4/FBXW7 expression was frequent in both EOGC and conventional gastric cancers.
- Loss of CDC4/FBXW7 expression significantly correlated with c-myc upregulation; no mutations were found.
Conclusions:
- Loss of CDC4/FBXW7 plays a role in both early-onset and conventional gastric carcinogenesis.
- c-myc overexpression is a likely oncogenic consequence of CDC4/FBXW7 loss in gastric cancer.
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