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：
10705735
负责人：
David Thomas
金额：
$ 36.82万
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/10705735
关键词：
Adult Affect Attitude BRCA2 gene Breast Cancer Biology Categories Characteristics Chromosome Mapping Clinical Clinical Trials Collection Communication Companions Confusion 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 Assessment 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 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：摘要/摘要平滑肌肉瘤（LMS）的稀有性已经详细研究了其遗传流行病学。 LMS发生与Li-Fraumeni综合征（LFS），由于种系TP53致病变异引起的遗传性癌综合征（PVS）和LMS也发生在视网膜母细胞瘤，这是另一个由于种系RB1引起的遗传性癌症综合征 PVS。最近对LMS患者的研究显示了DNA的其他种系突变损伤响应（DDR）途径，同样的途径在LMS肿瘤发生中起体细胞的作用。但是，LMS中的大多数家族风险仍然无法解释，并且LMS的诊断本身不会目前触发临床基因检测或风险评估。该项目组装了最大的LMS系列迄今为止，患者进行确定，全面的遗传流行病学调查。我们将确定并探索一系列潜在的癌症易感基因，以更充分地表征遗传风险，包括A 种系TP53变体的详细分析，这是LMS中最常见的突变基因。在AIM 1中，我们将使用犹他州人口数据库（UPDB）和国际肉瘤Kindred研究（ISK），以更好地定义 LMS患者家庭成员患癌症的风险。我们将询问这两个大型基于人群的大型和基于国际肉瘤的资源，用于探索LMS概率及其家人中癌症特定模式的资源寻找与LFS和其他癌症易感综合征的关联。在AIM 2中，我们将访问种系迄今为止，LMS最大的全基因组测序分析的700例LMS的DNA迄今使用了ISK 以及临床试验的病例作为该孢子的一部分。这项研究将创建当前的确定地图已知的癌症易感基因，还使用新型统计方法来识别新型基因和途径与LMS相关。在一项试验社会心理研究中，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回报。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交流和在高危亲属之间进行测试。在AIM 3中，我们将分析TP53基因型：表型相关性通过联合国际LFS注册表与可用的临床基因测试数据相结合的LFS家族，部分试图量化LMS风险并确定TP53中影响这种风险的遗传因素。完成在项目2中，我们将组装并分析一些最大的LMS患者集合（多达800个人）以及仔细询问的LMS患者，患有遗传癌的易感性，包括他们对基因检测的态度。我们在癌症调查团队的综合力量从人群科学家到临床癌症遗传学家的遗传学将有助于我们大大扩展我们的理解 LMS的遗传风险。