Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants
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,
Cynthia Schneider,
Heena Desai,
James T. Dove,
Diane T. Smelser,
Arnold J. Levine,
Kara N. Maxwell,
Douglas R. Stewart,
David J. Carey,
Sharon A. Savage
Affiliations
Kelvin C. de Andrade
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Corresponding author
Natasha T. Strande
Department of Genomic Health, Geisinger Clinic, Geisinger, Danville, PA, USA
Jung Kim
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Jeremy S. Haley
Department of Genomic Health, Geisinger Clinic, Geisinger, Danville, PA, USA
Jessica N. Hatton
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Megan N. Frone
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Payal P. Khincha
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Gretchen M. Thone
Department of Genomic Health, Geisinger Clinic, Geisinger, Danville, PA, USA
Uyenlinh L. Mirshahi
Department of Genomic Health, Geisinger Clinic, Geisinger, Danville, PA, USA
Cynthia Schneider
Division of Hematology/Oncology, Department of Medicine and Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Heena Desai
Division of Hematology/Oncology, Department of Medicine and Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
James T. Dove
Department of Genomic Health, Geisinger Clinic, Geisinger, Danville, PA, USA
Diane T. Smelser
Department of Genomic Health, Geisinger Clinic, Geisinger, Danville, PA, USA
Arnold J. Levine
Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA
Kara N. Maxwell
Division of Hematology/Oncology, Department of Medicine and Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Douglas R. Stewart
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
David J. Carey
Department of Genomic Health, Geisinger Clinic, Geisinger, Danville, PA, USA
Sharon A. Savage
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Summary: 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 ever developed a hematologic cancer. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand the population prevalence of germline TP53 variants and their associated cancer penetrance.
