Precision approaches to refining TP53-associated cancer risk

致病性TP53基因变异是遗传性癌症综合征Li-Fraumeni综合征(LFS)70%的基础 经典地与易患多种原发肿瘤有关，特别是肉瘤，脑，乳腺， 肾上腺皮质和其他恶性肿瘤发生在不寻常的早年。传统上，临床TP53检测仅限于 符合特定标准的个人和家庭。随着基于NGS的多基因面板检测的引入 (MGPT)，目前正在对大量不符合LFS标准的人进行TP53检测。范围更广 对TP53突变的MGPT检测引起了人们的担忧：1)突变的表型谱更广 携带者；以及2)在血液或唾液中发现的等位基因频率低于以下的TP53变异与临床的相关性 生殖系携带者的预期频率为50%。我们证明了异常克隆性扩张(ACE) 具有获得性致病TP53变异的造血细胞(克隆性造血细胞CH)导致许多 这类案件。血管紧张素转换酶/血管紧张素转换酶在健康人群中的出现频率随着年龄的增长而增加。 癌症幸存者在接受化疗后，与血液病风险增加有关 恶毒。在临床上，从体细胞TP53变异(ACE)中区分真正的胚系是至关重要的，因为临床上 其含义有很大不同。真胚系TP53突变携带者可能会承受心理、医学上的 以及打击个人和家庭癌症风险的财务成本，密集监测的负担，高 在不成比例的年轻时癌症死亡的风险以及可能将TP53变异传递给 后代。那些患有ACE/CH的患者可能会因血液系统恶性肿瘤或心脏病的风险增加而接受随访。 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。 调查人员将与Li-Fraumeni勘探联盟(LIFE)的同事和其他人合作 患者通过更广泛、更不可知的方法进行测试：商业基因测试 实验室，盖辛格MyCode®项目，对生殖系突变个体的快速研究，以及 Orien肿瘤/生殖系测序计划，以聚集具有TP53突变的最大个体队列 在血液或唾液及其亲属中。考虑到LFS的罕见，通过其他方式获得这一队列将是 成本过高且不切实际。在目标1中，我们将估计家庭中与TP53相关的特定部位的癌症风险 通过不可知测试方法进行鉴定，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TP53等位基因异质性和特定的遗传变异在以下方面的作用 这些癌症风险的修饰物。ACE将按照目标3中的描述进行单独描述，我们将排除 来自Aim 1和2分析的具有ACE而不是胚系TP53突变的先证者。 这些研究将提高我们区分生殖系TP53变异和相关变异的能力 ACE和阐明的基因-表型相关性将更好地定义与TP53相关的肿瘤 光谱和癌症风险，以帮助完善两组的临床管理建议。

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.