POT1 Tumor Susceptibility Research: A Broader Spectrum of Related Malignancies and Recommendations for Additional Screening Plans

Research Background

POT1 (Protection of Telomeres Protein 1) is an important component of the Shelterin telomere-binding complex, responsible for regulating telomere length. Some pathogenic variants (PVs) of the POT1 gene can lead to telomere elongation, genomic instability, and increased cancer risk. POT1 tumor predisposition syndrome (POT1-TPD) has an autosomal dominant inheritance pattern with unknown penetrance. It is associated with increased risks of cutaneous melanoma, chronic lymphocytic leukemia, angiosarcoma, and glioma. This study aims to describe a broader cancer phenotype associated with POT1-TPD.

Research Source

• Authors: Marta Baptista Freitas, Laurence Desmyter, Cindy Badoer, Guillaume Smits, Isabelle Vandernoot, Daphné T´kint de Roodenbeke
• Institutions: Centro Hospitalar Universitário de São João in Porto, Portugal, and several research centers in Brussels, Belgium.
• Publication: “European Journal of Human Genetics”, published in 2024.
• DOI: https://doi.org/10.1038/s41431-024-01611-0

Research Details

The study involved three families, two with four-generation pedigrees and one with a five-generation pedigree. The three index cases were referred to our genetic counseling center due to personal cancer history. Through clinical exome sequencing of 4867 genes associated with Mendelian disorders and genome sequencing including POT1 for one family member, three different POT1 pathogenic variants were identified. A total of 37 individuals were tested, with 22 cases of POT1 PV detected. In addition to the increased occurrence of POT1-TPD, a higher incidence of other types of cancer (other sarcomas, papillary thyroid cancer, early-onset prostate cancer, and leukemia) was observed.

Results and Conclusions

• Key Findings: These findings enhance our understanding of POT1 PVs and may play a role in defining future POT1 PV screening criteria, monitoring protocols for POT1 carriers (possibly including all types of sarcomas), and genetic counseling.

• Scientific and Practical Value: This study expands our knowledge of cancer types associated with POT1-TPD, potentially contributing to improved screening and monitoring plans for POT1 variant carriers, and providing more accurate information in genetic counseling services.

• Research Novelty: This study provides new scientific evidence on cancer types caused by POT1 gene variants, calling for a re-examination of existing POT1 gene screening and monitoring recommendations.

• Uniqueness of Research Subjects: Analysis of specific family members’ genomes revealed a broader tumor spectrum related to POT1-TPD.

This study emphasizes that the diagnosis of POT1-TPD may be underestimated by existing recommended criteria, calling for a re-evaluation of search conditions for POT1 PVs to improve the diagnosis rate of POT1-TPD.

Genetic Counseling and Monitoring Recommendations

Given the broader range of cancer types observed in the study, screening for POT1 mutations should be considered for all types of sarcomas. Pre-symptomatic testing was performed on family members in this study to determine the presence of POT1 mutations, and carriers were monitored according to current recommendations. One POT1 carrier was later diagnosed with a low-grade glioma, highlighting the importance of monitoring plans. It is suggested that we need more in-depth research on the potential carcinogenic spectrum of POT1 PVs, especially prospective large-scale patient cohort studies.