Genetic variation in POT1 and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study

PLoS One. 2020 Feb 10;15(2):e0228887. doi: 10.1371/journal.pone.0228887. eCollection 2020.


Background: Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm and inherited variation in telomere maintenance genes.

Methods: We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets.

Results: The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004).

Conclusions: Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Cancer Survivors
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Incidence
  • Introns
  • Longitudinal Studies
  • Male
  • Neoplasms, Second Primary / epidemiology
  • Neoplasms, Second Primary / genetics*
  • Polymorphism, Single Nucleotide
  • Proportional Hazards Models
  • Risk Factors
  • Shelterin Complex
  • Telomere Homeostasis / genetics
  • Telomere-Binding Proteins / genetics*
  • Thyroid Neoplasms / epidemiology
  • Thyroid Neoplasms / genetics*


  • POT1 protein, human
  • Shelterin Complex
  • Telomere-Binding Proteins