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Original research
POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families
  1. Erica Shen1,
  2. Joanne Xiu2,
  3. Giselle Y Lopez3,4,
  4. Rex Bentley3,4,
  5. Ali Jalali5,
  6. Amy B Heimberger6,
  7. Matthew N Bainbridge7,
  8. Melissa L Bondy8,
  9. Kyle M Walsh1,3,4
  1. 1 Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
  2. 2 Medical Affairs, Caris Life Sciences Inc, Phoenix, Arizona, USA
  3. 3 Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
  4. 4 Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, USA
  5. 5 Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA
  6. 6 Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  7. 7 The Genomic Institute, Rady Children's Hospital, San Diego, California, USA
  8. 8 Epidemiology and Population Health, Stanford University School of Medicine, Palo Alto, California, USA
  1. Correspondence to Dr Kyle M Walsh, Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA; kyle.walsh{at}


Background The shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored.

Methods We performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.

Results A total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10−20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10−3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation frequency versus other tumours (p=0.67).

Conclusions These results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.

  • POT1 mutation
  • telomere
  • hereditary cancer syndrome families
  • tert
  • atrx

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  • Contributors The following author contributions were made: substantial contributions to the conception (ES, JX and KMW) and design of the work (KMW), or the acquisition (KMW, GYL and JX), analysis or interpretation of data (ES, JX, RB, AJ, ABH, MNB, MLB and KMW); drafting the work or revising it critically for important intellectual content (all authors); final approval of the version published (all authors); agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved (all authors).

  • Funding This work was supported by a Distinguished Scientist Award from The Sontag Foundation (KMW) and by R01CA217105 from The National Cancer Institute (MLB and MNB).

  • Competing interests JX is an employee of Caris Life Sciences, Inc. ABH holds stock in, and is a paid advisory board member for, Caris Life Sciences, Inc. No other authors have identified potential conflicts of interest relevant to the manuscript.

  • Patient consent for publication Not required.

  • Ethics approval This study involved collection of existing data and publicly available diagnostic specimens, and the information gathering process precludes direct and indirect identification of subjects, which therefore exempts it from requiring institutional review board approval under HHS regulations at 45 CFR 46.101(b).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data may be obtained from a third party and are not publicly available. Data were obtained from Caris Life Sciences, Inc. Investigators with IRB approval for research may request these data by submitting a LOI to Caris using the following link: