American Association for Cancer Research
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Supplementary Figure S5 from The Common Germline TP53-R337H Mutation Is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model

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posted on 2023-03-31, 04:46 authored by John R. Jeffers, Emilia M. Pinto, Jerold E. Rehg, Michael R. Clay, Jinling Wang, Geoffrey Neale, Richard J. Heath, Guillermina Lozano, Enzo Lalli, Bonald C. Figueiredo, Alberto S. Pappo, Carlos Rodriguez-Galindo, Wenan Chen, Stanley Pounds, Raul C. Ribeiro, Gerard P. Zambetti

Gene set enrichment analysis of control and IR-treated WT and p53-R334H thymocytes.







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. 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.

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