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: 9815261
• 负责人: Christopher I. Amos
• 金额: $ 170.41万
• 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/9815261
• 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; Genetic screening method; 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 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; 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TP53基因变体是70％的Li-Fraumeni综合征（LFS），一种遗传性癌症综合征（LFS） 经典地与多种原发性肿瘤倾向相关，尤其是肉瘤，大脑，乳房， 异常早年的肾上腺皮质和其他恶性肿瘤。传统上，临床TP53测试仅限于 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 （MGPT），现在，正在对不符合LFS标准的大量人员进行TP53测试。更广泛 TP53突变的MGPT测试引起了人们对以下方面的关注：1）更广泛的表型频谱用于突变 载体； 2）在血液或唾液中鉴定出的TP53变体的临床相关性，等位基因频率以下 种系载体的预期频率为50％。我们证明了异常的克隆扩张（ACE） 具有获得的致病性TP53变体的造血细胞（克隆造血CH）负责许多 这样的情况。 ACE/CH，随着健康人群的增长，在频率越来越多的情况下观察到，并且 暴露于癌症存活中的化学疗法后，与血液学风险增加有关 恶性。从临床上讲，至关重要的是，从临床 含义大大不同。真正种系TP53突变的载体可能具有心理，医学 以及打击个人和家庭癌症风险的经济成本，强化监视的燃烧，高 年轻年龄不成比例的癌症死亡的风险以及可能通过TP53变体的重量 后代。可能会遵循患有ACE/CH的人，以增加血液学恶性肿瘤或心脏病的风险。 需要进行更多的研究以更好地量化TP53相关风险以阐明最佳管理。 调查人员将与Li-Fraumeni勘探联盟（Life）的同事和其他人合作 通过患者通过更广泛，更不可知的测试方法确定：商业基因测试 实验室，GeisingerMycode®项目，迅速研究生殖线突变的人以及 Orien肿瘤/种系测序项目，以组装TP53突变的最大人群 在血液或唾液及其亲戚中。考虑到LFS的稀有性，通过其他方式获得此队列将是 成本禁止和不切实际。在AIM 1中，我们将估计家庭中与TP53相关的现场特异性癌症风险 通过不可知论测试方法鉴定并研究其收集的肿瘤的肿瘤基因组特征 标本。在AIM 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符。 ACE将如AIM 3所述分别表征，我们将排除 来自AIM 1和2分析的ACE而不是种系TP53突变的概率。 这些研究将提高我们区分种系TP53变体和相关的能力 使用ACE，阐明的基因型 - 表型相关性将更好地定义与TP53相关的肿瘤 频谱和癌症风险有助于两组的临床管理建议。