Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.
Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.
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DOI：
10.1016/s1470-2045(21)00580-5
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发表时间：
2021-12
期刊：
影响因子：
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通讯作者：
Savage SA
中科院分区：
文献类型：
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作者：
de Andrade KC;Khincha PP;Hatton JN;Frone MN;Wegman-Ostrosky T;Mai PL;Best AF;Savage SA
Li-Fraumeni综合征（LFS）主要由致病性/可能致病性（P/LP）生殖系TP 53变体引起，是一种非渗透性、罕见的癌症易感综合征，从儿童期开始患癌症的风险非常高，包括一生中多次原发的风险。本研究旨在描述和量化P/LP生殖系TP 53变异个体的癌症发病率、模式和基因型-表型相关性。这项观察性队列研究是在2011年8月1日至2020年3月24日期间参加美国国家癌症研究所基于组织的纵向LFS研究的480名P/LP种系TP 53变异携带者中进行的。通过研究问卷获得个人和家族癌症史的数据，并通过医疗记录进行验证。根据功能丧失（LOF）和显性负效应（DNE）特性对变体进行分类。使用1975-2017年的监测、流行病学和最终结果（SEER）登记研究，将LFS相关癌症发病率与普通人群进行比较。采用家族聚集Cox回归模型和竞争风险方法评估癌症发病率。与SEER相比，P/LP生殖系TP 53变体携带者中任何癌症的标准化发病率在30岁之前最高（>60倍），50岁后仍高约10倍。在女性中，考虑到乳腺癌作为竞争风险，非乳腺首次癌症的概率大大低于任何首次癌症的概率（24.4% vs 50.4%，年龄33.7岁）。总体而言，与notDNE_notLOF和DNE_notLOF变体相比，DNE_LOF和notDNE_LOF变体与首次和第二次癌症的早期年龄相关。第一次癌症诊断较晚的携带者从第一次到第二次癌症的时间间隔较短。一些参与者在短时间内被诊断出多种癌症。这项研究为了解P/LP生殖系TP 53变异个体的癌症发病率和模式增加了重要的粒度。整合特定年龄段的癌症发病率估计，功能变异组的无癌生存率，降低风险的乳房切除术对女性癌症发病率的影响，以及后续恶性肿瘤的数据将是重要的，因为策略的制定，以优化这些人的癌症筛查和管理。美国国立卫生研究院癌症流行病学和遗传学系校内研究项目。
Li-Fraumeni syndrome (LFS), caused primarily by pathogenic/likely pathogenic (P/LP) germline TP53 variants, is a variably penetrant, rare cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primaries over the lifespan. This study aimed to characterize and quantify cancer incidence, patterns, and genotype-phenotype associations in individuals with P/LP germline TP53 variants. This observational cohort study was conducted on 480 carriers of P/LP germline TP53 variants enrolled in the National Cancer Institute’s referral-based longitudinal LFS study between August 1, 2011 and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorized based on both loss-of-function (LOF) and dominant-negative effect (DNE) properties. LFS-associated cancer incidences were compared with the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975–2017 registry. Cancer incidences were evaluated using family-clustered Cox-regression models and competing risk methods. The standardized incidence of any cancer in carriers of P/LP germline TP53 variants compared with SEER is highest up to age 30 years (>60-times higher), remaining ~10-times higher after age 50 years. In females, the probability of a non-breast first cancer, considering breast cancer as a competing risk, was substantially lower than that of any first cancer (24·4% vs 50·4% by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short time frame in some participants. This study adds important granularity to the understanding of cancer incidence and patterns in individuals with P/LP germline TP53 variants. Integration of age-range-specific cancer incidence estimates, cancer-free survival by functional variant group, impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancy will be important as strategies are developed to optimize cancer screening and management for these individuals. Intramural Research Program, Division of Cancer Epidemiology and Genetics, NIH.