The Common Germline TP53-R337H Mutation Is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model
| Autor: | Bonald C. Figueiredo, Jerold E. Rehg, Richard J. Heath, Alberto S. Pappo, Jinling Wang, Carlos Rodriguez-Galindo, Geoffrey Neale, Guillermina Lozano, Raul C. Ribeiro, Stanley Pounds, Wenan Chen, John R. Jeffers, Gerard P. Zambetti, Enzo Lalli, Emilia M. Pinto, Michael R. Clay |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Mutation Genetic counseling Mutant Cancer Endogeny Context (language use) Biology medicine.disease_cause medicine.disease Penetrance Germline 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis medicine Cancer research |
| Zdroj: | Cancer Research. 81:2442-2456 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-20-1750 |
| Popis: | The TP53-R337H founder mutation exists at a high frequency throughout southern Brazil and represents one of the most common germline TP53 mutations reported to date. It was identified in pediatric adrenocortical tumors in families with a low incidence of cancer. The R337H mutation has since been found in association with early-onset breast cancers and Li–Fraumeni syndrome (LFS). To study this variability in tumor susceptibility, we generated a knockin mutant p53 mouse model (R334H). Endogenous murine p53-R334H protein was naturally expressed at high levels in multiple tissues and was functionally compromised in a tissue- and stress-specific manner. Mutant p53-R334H mice developed tumors with long latency and incomplete penetrance, consistent with many human carriers being at a low but elevated risk for cancer. These findings suggest the involvement of additional cooperating genetic alterations when TP53-R337H occurs in the context of LFS, which has important implications for genetic counseling and long-term clinical follow-up. Significance: A p53-R334H knockin mouse serves as an important model for studying the most common inherited germline TP53 mutation (R337H) that is associated with variable tumor susceptibility. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|