PROJECT 2: Understanding the role of TP53 in LMS development

项目 2：了解 TP53 在 LMS 开发中的作用

• 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
• 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

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