Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants

作者：Kelvin C. de Andrade, Natasha T. Strande, Jung Kim, Jeremy S. Haley, Jessica N. Hatton, Megan N. Frone, Payal P. Khincha, Gretchen M. Thone, Uyenlinh L. Mirshahi, Cindy Schneider, Heena Desai, James Dove, Diane T. Smelser, Arnold J. Levine, Kara N. Maxwell, Douglas R. Stewart, David J. Carey, Sharon A. Savage · 发表于：Human Genetics and Genomics Advances · 年份：2023 · DOI：10.1016/j.xhgg.2023.100242 · 被引用次数：19 · 研究领域：Cancer-related Molecular Pathways、Epigenetics and DNA Methylation、Cancer Genomics and Diagnostics

Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥30%) TP53 variants in three cohorts: UK Biobank (UKB, n = 200,590), Geisinger (n = 170,503), and Penn Medicine Biobank (PMBB, n = 43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9 of 109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47 of 110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants was conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB. These estimates were calculated after excluding related individuals and accounting for the potential impact of clonal hematopoiesis by excluding heterozygotes who ev...