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.

致病性TP 53基因变异导致70%的Li-Fraumeni综合征（LFS），一种遗传性癌症综合征 与多发性原发性肿瘤，特别是肉瘤，脑，乳腺， 肾上腺皮质和其他恶性肿瘤在异常早期的年龄。传统上，临床TP 53检测仅限于 符合特定标准的个人和家庭。随着基于NGS的多基因面板测试的引入， （MGPT），TP 53测试现在正在对大量不符合LFS标准的人进行。更广泛 TP 53突变的MGPT检测引起了以下问题：1）突变的表型谱更广 携带者;和2）在血液或唾液中鉴定的TP 53变体的临床相关性，其中等位基因频率低于 生殖系携带者的50%预期频率。我们证明，异常克隆扩增（ACE）， 具有获得性致病性TP 53变体的造血细胞（克隆造血CH）负责许多 这样的案件。ACE/CH，在健康人群中随着年龄的增长观察到频率增加，以及 在癌症幸存者暴露于化疗后， 恶性肿瘤在临床上，从体细胞TP 53变体（ACE）中辨别真正的生殖系是至关重要的，因为临床上， 其影响大不相同。真正生殖系TP 53突变的携带者可能会承受心理，医学， 打击个人和家庭癌症风险的经济成本，强化监测的负担， 癌症死亡的风险在不成比例的年轻人和重量可能通过TP 53变异， 后代ACE/CH患者可随访血液系统恶性肿瘤或心脏病风险增加。 需要更多的研究来更好地量化TP 53相关风险，以阐明最佳管理。 研究人员将与Li-Fraumeni勘探联盟（LiFE）的同事和其他人合作 通过更广泛、更不可知的检测方法来确定患者：商业基因检测 实验室，Geisinger MyCode®项目，对生殖系突变个体的PROMPT研究，以及 ORIEN肿瘤/生殖系测序项目，以汇集最大的TP 53突变个体队列 在血液或唾液及其亲属中。考虑到LFS的罕见性，通过其他方式获得这一群体将是 成本过高且不切实际。在目标1中，我们将估计家庭中TP 53相关位点特异性癌症风险 通过不可知测试方法识别，并研究其收集的肿瘤中的肿瘤基因组特征 标本在目标2中，我们将研究TP 53等位基因异质性和特定遗传变异的作用， 这些癌症风险的调节剂。ACE将按照目标3中的描述进行单独表征，我们将排除 Aim 1和Aim 2分析中ACE而非种系TP 53突变的先证者。 这些研究将提高我们区分生殖系TP 53变异体和那些相关变异体的能力。 基因型-表型相关性的阐明将更好地定义TP 53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。