Apparently Heterozygous TP53 Pathogenic Variants May Be Blood Limited in Patients Undergoing Hereditary Cancer Panel Testing

Publication date: Available online 24 December 2019Source: The Journal of Molecular DiagnosticsAuthor(s): Jessica L. Mester, Sarah A. Jackson, Kristen Postula, Amy Stettner, Sheila Solomon, Jeffrey Bissonnette, Patricia D. Murphy, Rachel T. Klein, Kathleen S. HruskaHeterozygous (HET) TP53 pathogenic variants (PVs) are associated with Li-Fraumeni syndrome (LFS), a dominantly inherited condition causing high risk for sarcoma, breast, and other cancers. Recent reports described patients without features of LFS and apparently HET TP53 PVs in blood cells but not fibroblasts (FBs), suggesting the variant occurred sporadically during hematopoiesis and rose to high allele fraction through clonal expansion. To explore possible clonal hematopoiesis in patients undergoing hereditary cancer testing, FB testing was performed for patients with apparently HET or mosaic TP53 PVs identified in blood, oral rinse, or buccal specimens via next-generation sequencing panels. Among 291 individuals with TP53 PVs, 146 (50.2%) appeared HET and 145 (49.8%) were mosaic. Twenty-nine HET cases were proved constitutional through familial testing. FB testing was completed for 17 apparently HET and 36 mosaic patients. FB testing was positive in 11 of 17 apparently HET patients (64.7%), only one of whom met Chompret criteria. Of 36 mosaic patients, 5 (13.9%) were also mosaic in FBs, indicating constitutional mosaicism. Breast cancers in patients with constitutional TP53 PVs were diagnosed at younger ages (P ...
Source: The Journal of Molecular Diagnostics - Category: Pathology Source Type: research