see also:

• neoplasia / cancer / tumours

• a rare autosomal dominant germline loss-of-function mutations of POT1 (Protection of Telomeres 1) gene (on chromosome 7) which prevents the normal capping and regulation of telomeres and this results in abnormal lengthening of telemores and prevention of normal cell senescence apoptosis.
• this has been called POT1 Tumor Predisposition Syndrome (POT1-TPD)
• penetrance is currently unknown
• 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 length
• onset of tumours may be in late adolescence which suggests those with POT1 mutations may require regular screening from that age ¹⁾

• 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 cancers²⁾
  • 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 ³⁾
  • 1% of patients with myeloproliferative disorders

• the full risk spectrum is not clear as many POT1 mutation families have tumours which are also common in those without POT1 mutations
• increases lifetime risk of lymphoid malignancies 8 fold ⁴⁾
  • 17% will develop lymphoma by age 70yrs and 45% will develop a lymphoma by age 80⁵⁾
• increases risk of CLL 16-fold
• 7-fold increased risk of melanomas
• angiosarcomas
• thyroid cancer
  • ?Familial Non-Medullary Thyroid Cancer⁶⁾
• gliomas
• myeloproliferative disorders
• 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 ⁷⁾
• rarely, young adults may present with early-onset renal tumors, including papillary RCC and other renal malignancies, or early onset prostate cancer ⁸⁾
• patients may have a history of multiple different neoplasms
  • eg. a 63-year-old female who developed a sudden cough and was found to have a large adrenal mass abutting adjacent organs, along with an incidental pancreatic lesion. Her medical history was significant for renal cancer, uterine carcinosarcoma, pituitary adenoma, and chronic lymphocytic leukemia (CLL) and found to have an adrenal cortical carcinoma (ACC) ⁹⁾

• telomeres grow excessively long, which can be identified in clinical tests like flow-FISH
• most clinicians would probably order genetic testing for POT1 mutations (and probably include other oncogenes depending upon known family oncogenes or tumour profiles such as TP53, BRCA, etc)