PROJECT 2: Understanding the role of TP53 in LMS development

项目 2：了解 TP53 在 LMS 开发中的作用

基本信息

批准号：
10493630
负责人：
David Thomas
金额：
$ 32.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10493630
关键词：
Adult Affect Attitude BRCA2 gene Breast Cancer Biology Categories Characteristics Clinical Clinical Trials Collection Communication Companions DNA DNA Binding Domain DNA Damage DNA Repair Data Databases Development Diagnosis Disease ERCC2 gene Elements Family Family Cancer History Family member Foundations Future General Population Genes Genetic Genetic Predisposition to Disease Genetic Risk Genomics Genotype Germ-Line Mutation Goals Guidelines Hereditary Malignant Neoplasm Hereditary Neoplastic Syndromes Histologic Individual Inherited International International Agency for Research on Cancer Li-Fraumeni Syndrome Lifting Malignant Neoplasms Maps Medical Medical Genetics Mutate Mutation Outcome Ovarian Pancreas Pathogenicity Pathway interactions Patients Pattern Phenotype Play Population Population Database Predisposition Prevalence Prostate Psychosocial Assessment and Care RB1 gene Recording of previous events Registries Relative Risks Reporting Resources Retinoblastoma Risk Risk Estimate Risk Management Role Scientist Screening for cancer Second Primary Neoplasms Series Site Soft tissue sarcoma Statistical Methods Surveys Susceptibility Gene Syndrome TP53 gene Testing Therapeutic Utah Variant Work base cancer diagnosis cancer genetics cancer predisposition cancer risk case control clinically actionable cohort epidemiology study family management genetic epidemiology genetic information genetic risk assessment genetic risk factor genetic testing genome sequencing improved kindred leiomyosarcoma novel novel strategies phenotypic data population based proband psychosocial rare variant reference genome response sarcoma testing uptake tumor tumorigenesis whole genome

项目摘要

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 genetic risks for LMS.

项目 2：总结/摘要平滑肌肉瘤（LMS）的罕见性使得对其遗传流行病学的详细研究变得困难。发生 LMS Li-Fraumeni 综合征 (LFS)，一种由种系 TP53 致病性变异引起的遗传性癌症综合征 (PV)，LMS 也会发生在视网膜母细胞瘤中，视网膜母细胞瘤是另一种由种系 RB1 引起的遗传性癌症综合征光伏发电。最近对 LMS 患者的有限研究揭示了 DNA 中额外的种系突变损伤反应 (DDR) 途径，该途径已知在 LMS 肿瘤发生中发挥体细胞作用。然而，LMS 的大部分家族风险仍然无法解释，并且 LMS 的诊断本身并不能解释 LMS 的风险。目前触发临床基因检测或风险评估。该项目组装了最大系列的 LMS 迄今为止，患者已进行了明确且全面的遗传流行病学调查。我们将识别并探索一系列潜在的癌症易感基因，以更全面地表征遗传风险，包括对种系 TP53 变体（LMS 中最常见的突变基因）的详细分析。在目标 1 中，我们将利用犹他州人口数据库 (UPDB) 和国际肉瘤亲属研究 (ISKS)，以更好地定义 LMS 患者的家庭成员患癌症的风险。我们将审问这两大人口基基于国际肉瘤的资源，用于探索 LMS 先证者及其家人的癌症特异性模式寻找与 LFS 和其他癌症易感综合征的关联。在目标 2 中，我们将访问种系利用 ISKS 对 700 个 LMS 病例进行 DNA 分析，进行迄今为止最大的 LMS 全基因组测序分析以及作为此 SPORE 一部分的临床试验案例。这项研究将绘制出目前的明确地图已知的癌症易感基因，并使用新的统计方法来识别新的基因和途径与 LMS 相关。在一项试点社会心理研究中，将评估全球 LMS 患者的态度关于种系基因组学和遗传信息的返回。在 LMS 患者中发现携带致病性变异（PV）在癌症易感基因中，我们将探索心理社会结果以及沟通和高危亲属接受检测。在目标 3 中，我们将分析 TP53 基因型：表型相关性通过结合国际 LFS 登记和可用的临床基因检测数据，患有 LMS 的 LFS 家庭，部分目的是寻求量化 LMS 风险并确定 TP53 中影响该风险的遗传因素。完成时在项目 2 中，我们将收集并分析一些最大的 LMS 患者总体数据集（最多 800 人）以及经过仔细询问的已确定具有遗传性癌症倾向的 LMS 患者，包括他们对基因检测的态度。我们癌症研究团队的综合实力遗传学，从人口科学家到临床癌症遗传学家，将帮助我们极大地扩展我们的理解 LMS 的遗传风险。