Cancer Incidence, Patterns, and Genotype-Phenotype Associations in an Observational Cohort Study of Individuals with Pathogenic or Likely Pathogenic Germline TP53 Variants
Abstract
Background: 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. Methods: 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. Findings: 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…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
Read the paper
Related studies
- Improving sleep quality leads to better mental health: A meta-analysis of randomised controlled trials
- Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study
- Occupation and risk of severe COVID-19: prospective cohort study of 120,075 UK Biobank participants
- Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study
- Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study
- Lifestyle risk factors, inflammatory mechanisms, and COVID-19 hospitalization: A community-based cohort study of 387,109 adults in UK
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.