see also:

• neoplasia / cancer / tumours

• a rare autosomal dominant germline loss-of-function mutations of POT1 (Protection of Telomeres 1) gene which prevents the normal capping and regulation of telomeres and this results in abnormal lengthening of telemores and prevention of normal cell senescence apoptosis.
• long-lived cells have more time to acquire cancer-causing mutations, which then persist and expand over generations of cell division - POT1 variant carriers have subclinical lymphoid clonality
• some cancers are also due to somatic POT1 mutations
• POT1 encodes a single-stranded DNA (ssDNA) binding protein that forms part of the shelterin complex, a group of proteins that have functions in telomere protection by allowing cells to distinguish the ends of chromosomes from sites of DNA damage, and also function to regulate telomere lengt

• occurs in ~1 in 3000 people without cancers and in 0.12% of those with cancers
• accounts for:
  • 0.5% to 1% of patients with multiple different cancers¹⁾
  • up to 5% of CLL cases
  • 16-23% of angiosarcoma cases
  • 2.4-4% of familial melanoma patients and 0.5% of all melanoma patients ²⁾
  • 1% of patients with myeloproliferative disorders

• increases lifetime risk of lymphoid malignancies 8 fold ³⁾
• 17% will develop lymphoma by age 70yrs and 45% will develop a lymphoma by age 80⁴⁾
• increases risk of CLL 16-fold
• 7-fold increased risk of melanomas
• sarcomas
• thyroid cancer
  • ?Familial Non-Medullary Thyroid Cancer⁵⁾
• gliomas
• myelodysplastic disorder
• polycythaemia
• essential thrombocytosis
• chronic lymphocytosis
• “familial clonal hematopoiesis” syndrome, where the inherited POT1 mutation leads to the early onset of Clonal Hematopoiesis of Indeterminate Potential (CHIP), frequently driven by somatic JAK2 V617F mutations ⁶⁾

• telomeres grow excessively long, which can be identified in clinical tests like flow-FISH