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Description

Project Summary/Abstract The purpose of this supplement is to rigorously characterize a mutation in the TP53 tumor suppressor gene that was identified from a patient enrolled in our clinical trial “Project Inherited Cancer Risk”, which is supported by the Kentucky Pediatric Cancer Trust Fund. This supplement represents a bedside-to-bench translational project to establish that a specific mutation in the TP53 gene (T235I) leads to loss of function of the p53 tumor suppressor protein. We reason that TP53-T253I is pathogenic because it was identified in germline tissue of an eight month old who presented with adrenocortical carcinoma (ACC), a tumor highly suggestive of Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome caused by germline deficiency of p53 function. This work is important not only to inform the oncologic and cancer biology community about genotype-phenotype effects of TP53 variants, but these studies may also impact our patient and her family for their long-term management as cancer- predisposed individuals. Since this T253I mutation is not yet reported as pathogenic, there is the concern that there may be reluctance on the part of health insurance carriers to cover the cancer surveillance scans, visits and tests required for optimal care of the patient and her affected family members. Our goal is to establish by a combination of biochemical and molecular assays that the T253I mutation in TP53 negatively impacts canonical p53 cellular responses such as damage-induced transcriptional regulation, cell cycle checkpoint and apoptosis. We will (1) develop suitable cell line models to study the TP53-T253I mutation, (2) determine whether the TP53- T253I mutation impacts p53-DNA interactions and transcriptional regulation, and (3) determine whether the TP53-T253I mutation impacts damage-induced p53 signaling, cell cycle arrest and apoptosis. Our intent is to publish the patient’s clinical history along with our research findings to establish that TP53-T253I is pathogenic.
StatusActive
Effective start/end date7/1/226/30/24

Funding

  • KY Cabinet for Health and Family Services: $250,000.00

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