Precision approaches to refining TP53-associated cancer risk

改善 TP53 相关癌症风险的精准方法

• 批准号: 10020352
• 负责人: Christopher I. Amos
• 金额: $ 171.33万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020352
• 关键词: Address; Age; Alleles; Base Sequence; Blood; Brain; Breast; Breast Sarcoma; Cancer Family; Cancer Survivor; Cancer-Predisposing Gene; Caring; Cells; Cessation of life; Characteristics; Clinical; Clinical Management; Clonal Evolution; Clonal Expansion; Collection; Constitutional; Diagnostic tests; Disease; Elderly; Exposure to; Family; Financial cost; Frequencies; Gene Frequency; Genes; Genetic Variation; Genomics; Genotype; Germ-Line Mutation; Heart Diseases; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hereditary Neoplastic Syndromes; Heterogeneity; High-Risk Cancer; Histologic; Individual; Inherited; Laboratories; Li-Fraumeni Syndrome; Malignant Neoplasms; Marrow; Medical Care Costs; Modification; Molecular; Molecular Genetics; Mosaicism; Multiple Primary Neoplasms; Mutation; Myelogenous; Natural History; Neoplasms; Other Genetics; Pathogenicity; Patient Care; Patients; Penetrance; Phenotype; Population; Population-Based Registry; Positioning Attribute; Precision Medicine Initiative; Predisposition; Premalignant Cell; Prevalence; Recommendation; Registries; Research; Research Personnel; Risk; Role; Saliva; Site; Specimen; Statistical Models; Syndrome; TP53 gene; Testing; Tissues; Ursidae Family; Variant; Weight; base; cancer cell; cancer risk; chemotherapy; clinical care; clinically relevant; cohort; cost; exome; genetic disorder diagnosis; genetic panel test; genetic testing; genetic variant; genomic profiles; high risk; improved; insight; lifestyle factors; loss of function; malignant breast neoplasm; mutation carrier; next generation; next generation sequencing; novel; offspring; patient oriented; personalized approach; polygenic risk score; population based; proband; prospective; psychologic; recruit; sarcoma; translational impact; tumor

Pathogenic TP53 gene variants underlie 70% of Li-Fraumeni Syndrome (LFS), a hereditary cancer syndrome classically associated with predisposition to multiple primary neoplasms, particularly sarcoma, brain, breast, adrenocortical and other malignancies at unusually early ages. Traditionally, clinical TP53 testing was limited to individuals and families who met specific criteria. With the introduction of NGS-based multi-gene panel testing (MGPT), TP53 testing is now being performed on large numbers of people who do not meet LFS criteria. Broader MGPT testing for TP53 mutations has raised concerns about:1) a broader phenotypic spectrum for mutation carriers; and 2) the clinical relevance of TP53 variants identified in blood or saliva with allele frequencies below the 50% expected frequency for a germline carrier. We demonstrated that aberrant clonal expansions (ACE) of hematopoietic cells (clonal hematopoiesis CH) with an acquired pathogenic TP53 variant is responsible for many such cases. ACE/CH, which is observed at increasing frequency with advancing age in healthy populations, and after exposure to chemotherapy in cancer survivors, has been associated with increased risk of hematologic malignancy. Clinically, it is critical to discern true germline from somatic TP53 variants (ACE), since the clinical implications differ substantially. Carriers of true germline TP53 mutations may bear the psychological, medical and financial costs of striking personal and family cancer risks, the burden of intensive surveillance, the high risks of cancer deaths at disproportionately young ages and the weight of possibly passing TP53 variants to offspring. Those with ACE/CH may be followed for increased risk of hematologic malignancy or heart disease. More research is needed to better quantify TP53 associated risks to clarify optimal management. The investigators will partner with colleagues from the Li-Fraumeni Exploration Consortium (LiFE), and others with patients ascertained through broader, more agnostic approaches to testing: commercial genetic testing laboratories, the Geisinger MyCode® project, the PROMPT study of individuals with germline mutations, and the ORIEN tumor/germline sequencing project, to assemble the largest cohort of individuals with a TP53 mutation in blood or saliva and their relatives. Given the rarity of LFS, acquiring this cohort through other means would be cost prohibitive and impracticable. In aim 1, we will estimate the TP53-related site-specific cancer risks in families identified through agnostic testing approaches and study tumor genomic characteristics in their collected tumor specimens. In aim 2, we will investigate the roles of TP53 allelic heterogeneity and specific genetic variation as modifiers of these cancer risks. ACE will be characterized separately as described in aim 3, and we will exclude probands with ACE rather than germline TP53 mutations from Aim 1 and 2 analyses. These studies will improve our ability to distinguish between germline TP53 variants and those associated with ACE, and the genotype-phenotype correlations elucidated will better define the TP53-associated tumor spectrum and cancer risks to help refine clinical management recommendations for both groups.

70% 的 Li-Fraumeni 综合征 (LFS)（一种遗传性癌症综合征）的致病性 TP53 基因变异是其根源 通常与多种原发性肿瘤的易感性相关，特别是肉瘤、脑瘤、乳腺癌、 传统上，临床 TP53 检测仅限于异常早期的肾上腺皮质和其他恶性肿瘤。 随着基于 NGS 的多基因面板测试的引入，满足特定标准的个人和家庭。 (MGPT)，目前正在对大量不符合 LFS 更广泛标准的人进行 TP53 测试。 TP53 突变的 MGPT 检测引起了人们对以下方面的担忧：1) 更广泛的突变表型谱 携带者；和 2) 在血液或唾液中鉴定出的等位基因频率低于的 TP53 变异的临床相关性 我们证明了种系携带者的 50% 预期频率。 具有获得性致病性 TP53 变异的造血细胞（克隆性造血 CH）导致许多 此类病例随着健康人群年龄的增长而出现频率增加，以及 癌症幸存者接受化疗后，与血液学风险增加相关 临床上，从体细胞 TP53 变异 (ACE) 中辨别真正的种系至关重要，因为临床 真正种系 TP53 突变的携带者可能会承受心理、医学方面的影响。 消除个人和家庭癌症风险的经济成本、强化监测的负担、高风险 年轻时癌症死亡的风险以及可能将 TP53 变异传递给 那些患有 ACE/CH 的后代可能会被追踪，以发现血液恶性肿瘤或心脏病的风险增加。 需要更多的研究来更好地量化 TP53 相关风险，以阐明最佳管理。 研究人员将与 Li-Fraumeni 勘探联盟 (LiFE) 和其他机构的同事合作 通过更广泛、更不可知的测试方法来确定患者：商业基因测试 实验室、Geisinger MyCode® 项目、对具有种系突变的个体的 PROMPT 研究以及 ORIEN 肿瘤/种系测序项目，汇集最大的 TP53 突变个体队列 鉴于 LFS 的稀有性，通过其他方式获取该群体是不可能的。 在目标 1 中，我们将评估家庭中与 TP53 相关的特定位点癌症风险。 通过不可知测试方法识别并研究收集的肿瘤中的肿瘤基因组特征 在目标 2 中，我们将研究 TP53 等位基因异质性和特定遗传变异的作用： 这些癌症风险的修饰因素将按照目标 3 中的描述进行单独表征，并且我们将排除这些因素。 根据 Aim 1 和 2 分析，先证者具有 ACE 而不是种系 TP53 突变。 这些研究将提高我们区分种系 TP53 变异和相关变异的能力 与 ACE 结合，阐明的基因型-表型相关性将更好地定义 TP53 相关肿瘤 频谱和癌症风险，以帮助完善两组的临床管理建议。