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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Comprehensive characterization of genes associated with the TP53 signal transduction pathway in various tumors
Shumpei Ohnami1, Keiichi Ohshima2, Takeshi Nagashima3,4
1Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan. s.onami@scchr.jp.
Abstract:
The TP53 signal transduction pathway is an attractive target for cancer treatments. In this study, we conducted a comprehensive molecular evaluation of 907 patients with cancer in Japan to identify genomic alterations in the TP53 pathway. TP53 mutations were frequently detected in many cancers, except melanoma, thymic tumors, gastrointestinal stromal tumors, and renal cancers. The frequencies of non-synonymous single nucleotide variants (SNVs) in the TP53 family members TP63 and TP73 were relatively low, although genes with increased frequencies of SNVs were as follows: PTEN (11.7%) in breast cancer, CDKN2A (11.1 and 9.6%) in pancreas and head and neck cancers, and ATM (18.0 and 11.1%) in liver and esophageal cancers. MDM2 expression was decreased or increased in patients with mutant or wild-type TP53, respectively. CDKN1A expression was increased with mutant TP53 in head and neck cancers. Moreover, TP63 overexpression was characteristically observed in squamous cell carcinomas of the lung, esophagus, and head and neck region. Additionally, overexpression of TP63 and TP73 was frequently observed in thymomas. Our results reveal a spectrum of genomic alterations in the TP53 pathway that is characteristic of many tumor types, and these data may be useful in the trials of targeted therapies.
Insights
Genomic alterations in the TP53 pathway are common across many cancers, offering potential targets for new cancer therapies. This study evaluated 907 Japanese cancer patients, revealing specific TP53 pathway mutations and expression changes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The TP53 pathway is a crucial regulator of cellular responses to stress and DNA damage.
- Dysregulation of the TP53 pathway is implicated in the development and progression of numerous cancers.
- Targeting the TP53 pathway represents a promising strategy for novel cancer therapeutics.
Purpose of the Study:
- To conduct a comprehensive molecular evaluation of the TP53 pathway in a large cohort of Japanese cancer patients.
- To identify specific genomic alterations and expression patterns within the TP53 pathway across diverse cancer types.
- To provide insights into the potential utility of TP53 pathway alterations as biomarkers for targeted therapy selection.
Main Methods:
- Molecular evaluation of 907 patients with various cancer types in Japan.
- Analysis of TP53 mutations and single nucleotide variants (SNVs) in TP53 family members (TP63, TP73) and other pathway genes (PTEN, CDKN2A, ATM).
- Assessment of gene expression levels for MDM2, CDKN1A, TP63, and TP73 in relation to TP53 status.
Main Results:
- TP53 mutations were frequently observed in most cancer types, with notable exceptions including melanoma and renal cancers.
- Elevated SNV frequencies were identified in PTEN (breast cancer), CDKN2A (pancreas, head and neck cancers), and ATM (liver, esophageal cancers).
- MDM2 expression inversely correlated with TP53 mutation status, while CDKN1A expression increased with mutant TP53 in head and neck cancers. TP63 overexpression was characteristic of squamous cell carcinomas and thymomas.
Conclusions:
- The study identified a diverse range of TP53 pathway genomic alterations specific to various tumor types.
- These findings highlight the broad relevance of the TP53 pathway in cancer pathogenesis.
- The characterized alterations provide a foundation for developing and implementing targeted therapies directed at the TP53 pathway in clinical trials.
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