Clinical Description
POT1 tumor predisposition (POT1-TPD) is associated with an increased risk for multiple cutaneous melanomas, sarcomas (particularly cardiac angiosarcomas), chronic lymphocytic leukemia (CLL), and gliomas. Additional cancers have been reported in individuals with a germline POT1 pathogenic variant. However, due to limited data it is unclear if these cancers are specifically associated with POT1 germline pathogenic variants. The general experience, however, is that there is a great diversity of tumor types within and between families.
Cutaneous melanoma is the most commonly reported malignancy in individuals with POT1-TPD. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years [Robles-Espinoza et al 2014, Shi et al 2014]. Multiple synchronous or metachronous primary cutaneous melanomas are common, with reports ranging from two primary melanomas to up to 20 primary melanomas [Robles-Espinoza et al 2014; Maas et al 2024; T Else, personal observation]. The time between diagnoses of first and second melanoma varies significantly (average: ~9 years).
Sarcoma. Pathogenic germline POT1 variants have been identified in individuals and families with sarcomas, with some families meeting Li-Fraumeni-like (LFL) criteria. In particular, POT1 pathogenic variant p.Arg117Cys has been reported in individuals with cardiac angiosarcoma and cardiac sarcoma [Calvete et al 2017]. Other individuals and families with POT1-TPD have developed osteosarcoma and non-cardiac angiosarcoma [Calvete et al 2015, Herrera-Mullar et al 2023, Abu Shtaya et al 2024, Baptista-Freitas et al 2024].
CLL. Disease-associated POT1 variants have been identified in rare instances of familial CLL. POT1 variants have been identified on somatic testing of CLL (tumor tissue); germline POT1 molecular testing can distinguish somatic and germline variants.
Glioma. Two families with more than one individual with glioma were found to have a germline POT1 pathogenic variant [Bainbridge et al 2014]. One or more individuals in these families presented with oligodendroglioma, suggesting a glioma type-specific susceptibility in these families.
Thyroid cancer has also been suggested to be part of POT1-TPD [Srivastava et al 2020, DeBoy et al 2024]. Germline POT1 pathogenic variants have been observed in 1.5% of selected individuals with papillary thyroid cancer (PTC), meeting criteria for familial PTC, multifocal PTC, and/or young-onset PTC, and 0.7% of unselected individuals with PTC [DeBoy et al 2024]. Individuals with a germline POT1 pathogenic variant had ultra-long telomere length. The pedigrees were felt to demonstrate genetic anticipation, as successive generations had longer telomere length than their parents and developed more cancers at younger ages.
Clonal hematopoiesis.
DeBoy et al [2024] found that excessively long telomeres in POT1 heterozygotes conferred a predisposition to lymphoid and myeloid clonal hematopoiesis. Twenty-eight percent (5/18) of individuals with a POT1 pathogenic variant had a T-cell clonality, including cutaneous T-cell lymphoma and large T-cell lymphoma. Sixty-seven percent (8/12) had clonal hematopoiesis of indeterminate potential. Of note, Lim et al [2022] found POT1 germline variants in 1% of individuals with myeloproliferative neoplasms.
Other cancers. Several other benign and malignant neoplasias have been reported in individuals with a germline POT1 variant [T Else, personal observation]; data are too limited to determine if the POT1 variant is causative.
Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been confirmed.
The p.Arg117Cys
POT1 variant has been reported in three families with LFL syndrome in which members had cardiac angiosarcoma, in one family with LFL syndrome in which a member had breast angiosarcoma, and in one individual with cardiac sarcoma in the absence of family history [Calvete et al 2015, Calvete et al 2017].
Penetrance
The penetrance of POT1-TPD is currently unknown. Initial studies suggest a very high penetrance but are subject to a selection bias for research cohorts/families. In more than half of reported families only the proband was tested. Many individuals with germline POT1 variants were ascertained based on a strong family history of cancer from tumor-specific consortiums (e.g., The Gliogene Consortium, UK National Study of Colorectal Cancer Genetics, UK Familial Melanoma Study).