# PROJECT 2:   Understanding the role of TP53 in LMS development

> **NIH NIH P50** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $327,523

## Abstract

Project 2: Summary/Abstract
The rarity of leiomyosarcoma (LMS) has made detailed study of its genetic epidemiology difficult. LMS occurs
with Li-Fraumeni Syndrome (LFS), a hereditary cancer syndrome due to germline TP53 pathogenic variants
(PVs), and LMS also occurs with Retinoblastoma, another hereditary cancer syndrome due to germline RB1
PVs. Recent limited studies of patients with LMS have revealed additional germline mutations in the DNA
damage response (DDR) pathway, the same pathway known to play a somatic role in LMS tumorigenesis.
However, the majority of familial risk in LMS remains unexplained and a diagnosis of LMS by itself does not
currently trigger clinical genetic testing or risk assessment. This project assembles the largest series of LMS
patients to date to perform a definitive and comprehensive genetic epidemiology survey. We will identify and
explore a range of potential cancer predisposition genes to more fully characterize the genetic risk, including a
detailed analysis of germline TP53 variants, the most commonly mutated gene in LMS. In Aim 1, we will utilize
the Utah Population Database (UPDB) and the International Sarcoma Kindred Study (ISKS) to better define the
risk for cancer in family members of LMS patients. We will interrogate these two large population-based and
international sarcoma-based resources to explore cancer-specific patterns in LMS probands and their families
to look for associations with LFS and other cancer predisposition syndromes. In Aim 2, we will access germline
DNA on 700 cases of LMS for the largest whole genome sequencing analysis of LMS to date, utilizing the ISKS
as well as cases from clinical trials as part of this SPORE. This study will create a definitive map of currently
known cancer predisposition genes and also use novel statistical methods to identify novel genes and pathways
associated with LMS. In a pilot psychosocial study, attitudes of LMS patients across the globe will be assessed
about germline genomics and return of genetic information. In LMS patients found to carry a pathogenic variant
(PV) in a cancer predisposition gene, we will explore psychosocial outcomes along with communication and
uptake of testing among at-risk relatives. In Aim 3, we will analyze the TP53 genotype:phenotype correlations in
LFS families with LMS through combined international LFS registries with clinical genetic testing data available,
in part seeking to quantify LMS risk and to identify genetic factors in TP53 affecting that risk. At the completion
of Project 2, we will have assembled and analyzed some of the largest collections of LMS patients in general
(up to 800 individuals) as well as carefully interrogated LMS patients with identified genetic cancer predisposition,
including their attitudes toward genetic testing. The combined strength of our investigative team in cancer
genetics, from population scientists to clinical cancer geneticists, will help us to greatly expand our understanding
of the ge...

## Key facts

- **NIH application ID:** 10493630
- **Project number:** 1P50CA272170-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Thomas
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $327,523
- **Award type:** 1
- **Project period:** 2022-09-16 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10493630

## Citation

> US National Institutes of Health, RePORTER application 10493630, PROJECT 2:   Understanding the role of TP53 in LMS development (1P50CA272170-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10493630. Licensed CC0.

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