PROJECT 2: Understanding the role of TP53 in LMS development

项目2：摘要/摘要 平滑肌肉瘤（LMS）的罕见性使其遗传流行病学的详细研究变得困难。LMS发生 Li-Fraumeni综合征（LFS），一种由生殖系TP 53致病性变异引起的遗传性癌症综合征 (PVs)LMS也发生在视网膜母细胞瘤中，这是另一种遗传性癌症综合征， 肺静脉最近对LMS患者的有限研究揭示了DNA中的额外种系突变， 损伤反应（DDR）途径，已知在LMS肿瘤发生中发挥体细胞作用的相同途径。 然而，大多数LMS的家族性风险仍然无法解释，LMS的诊断本身并不 目前已启动临床基因检测或风险评估。该项目汇集了最大的LMS系列 对迄今为止的患者进行明确和全面的遗传流行病学调查。我们将查明和 探索一系列潜在的癌症易感基因，以更全面地描述遗传风险，包括 详细分析生殖系TP 53变体，LMS中最常见的突变基因。在目标1中，我们将利用 犹他州人口数据库（CDB）和国际肉瘤亲缘研究（ISKS），以更好地定义 LMS患者家庭成员的癌症风险。我们将审问这两个庞大的人口基础和 基于肉瘤的国际资源，以探索LMS先证者及其家族的癌症特异性模式 寻找LFS和其他癌症易感综合征之间的联系。在目标2中，我们将获得生殖细胞 利用ISKS对700例LMS进行迄今为止最大规模的LMS全基因组测序分析 以及临床试验中的病例，作为此SPORE的一部分。这项研究将创建一个明确的地图， 已知的癌症易感基因，并且还使用新的统计方法来鉴定新的基因和途径 与LMS相关在一项试点心理社会研究中，将评估地球仪内LMS患者的态度 关于生殖细胞基因组学和遗传信息的回归。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沿着沟通， 在有风险的亲属中进行检测。在目标3中，我们将分析TP 53基因型：表型相关性， 通过联合国际LFS登记处获得的LMS LFS家族临床基因检测数据， 部分地寻求量化LMS风险并鉴定TP 53中影响该风险的遗传因素。完成时 在项目2中，我们将收集和分析一些最大的LMS患者集合 (up 800人）以及仔细询问具有确定的遗传癌症易感性的LMS患者， 包括他们对基因检测的态度。我们癌症调查团队的综合实力 遗传学，从人口科学家到临床癌症遗传学家，将帮助我们大大扩展我们的理解， LMS的遗传风险。

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.