# TP53 Germline Mutations: Beyond LFS

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $366,000

## Abstract

Project Summary
This proposal addresses Provocative Question 1 “What molecular mechanisms influence disease penetrance
in individuals who inherit a cancer susceptibility gene?” Li-Fraumeni Syndrome (LFS) is a rare, inherited
disorder that leads to a higher risk of breast cancer, soft tissue sarcoma, osteosarcoma, brain tumor (including
glioma), adrenal cortical carcinoma, and other cancers. TP53, encoding the p53 tumor suppressor, is mutated
in ~75% of LFS families. TP53 mutations in LFS patients occur in the coding sequence (CDS) and produce
mutant p53 proteins that lack most or all normal tumor-suppressive functions and often confer oncogenic
properties. Beyond LFS mutants, over 200 naturally occurring germline mutants of TP53 are known, yet only a
few of them cause measurable perturbation of p53 function. Recent reports demonstrate that a single
nucleotide polymorphism in a TP53 noncoding region predisposes carriers to multiple types of cancer including
glioma, neuroblastoma, skin basal cell carcinoma, esophageal squamous cell carcinoma, prostate cancer, and
colorectal adenoma. As such, cancer susceptibility of this p53 noncoding mutant does not strictly mirror that of
p53 germline mutations in LFS patients. Specifically, this noncoding mutant confers no increased risk of
breast cancer, the most common LFS tumor, whereas it shares similarity with LFS mutants in glioma
predisposition. This p53 mutant is positioned uniquely among known cancer-susceptibility alleles in that it is
noncoding and present at higher frequency (~1 in 50 in general populations, i.e., over 6 million Americans and
100 million people worldwide carry this mutant). We hypothesize that the moderate reduction of p53
activity by the noncoding mutant predisposes carriers to glioma but not breast cancer. In this study, we
will employ mouse models and cell lines to ascertain the causative role of this p53 noncoding mutant in cancer
by comparing it with an LFS coding sequence mutant. In Aim 1, we will determine whether the p53 mutant
increases glioma development in mice. In Aim 2, we will determine the role of this mutant in mammary tumor
development in mice and in human breast epithelial cell transformation. In Aim 3, we will dissect the
mechanisms of the p53 PAS mutant in tumorigenesis in comparison with an LFS mutant using mammary stem
cells and neural stem cells. Data generated from this study will reveal the biological and pathologic function of
p53 germline mutants beyond its established role in LFS. This project has potentially broad and far-reaching
significance in that our findings will reveal mechanistic causal connections between germline variation and
tissue-specific cancer penetrance.

## Key facts

- **NIH application ID:** 10151546
- **Project number:** 5R01CA219556-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Yong Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2019-10-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151546

## Citation

> US National Institutes of Health, RePORTER application 10151546, TP53 Germline Mutations: Beyond LFS (5R01CA219556-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151546. Licensed CC0.

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