Clinical, genetic, and familial features of POT1 tumor predisposition syndrome

BACKGROUND: Protection of telomere 1 (POT1) tumor predisposition syndrome (POT1-TPD) is a hereditary leukemia syndrome that is identified in ∼5% of patients with chronic lymphocytic leukemia (CLL) and is characterized by a predisposition to other cancers, including gliomas, melanomas, and angiosarcomas. This study reports clinical and genetic characteristics of a large cohort of individuals with POT1-TPD. MATERIALS AND METHODS: Individuals with pathogenic/likely pathogenic germline POT1 variants referred to the Hereditary Hematologic Malignancy Clinic at The University of Texas MD Anderson Cancer Center were included. Individuals with variants of uncertain significance were included if found to have telomeres >90th percentile of age-predicted length. RESULTS: Twenty-four individuals in 17 families were identified. At referral, 11 (46%) had CLL and one (4%) had monoclonal B-cell lymphocytosis (MBL). The remaining 12 individuals had no history of CLL/MBL; however, four (33%) were discovered to have MBL at the time of referral. Among the 17 families, melanoma (47%), CLL (35%), and glioblastoma (18%) were prevalent. Five families had telomere length testing (31%), with lymphocyte telomere lengths >99th percentile in 60% and >90th percentile in 100%. Patients with CLL (n = 11) had a median age at diagnosis of 55 years (range, 29-68). A total of 82% had diploid karyotype, 64% had del13q by fluorescence in situ hybridization, and 60% had mutated immunoglobulin heavy chain variable region. Five patients (45%) received treatment for CLL, with a median time-to-treatment of 4.5 years (95% CI, 4.3-4.6). CONCLUSION: This analysis provides insights into the clinical features and familial patterns of malignancy of individuals with POT1-TPD. Identification through genetic counseling and augmented cancer screening is paramount.