Long telomeres and cancer risk: the price of cellular immortality

J Clin Invest. 2019 Aug 5;129(9):3474-3481. doi: 10.1172/JCI120851.

Abstract

The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. Growing evidence shows that there are disease processes that are caused by both short and long telomere length extremes. The genetic basis of these short and long telomere syndromes may be linked to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through differential effects on telomere length. Short telomere syndromes have a predominant degenerative phenotype marked by organ failure that most commonly manifests as pulmonary fibrosis and are associated with a relatively low cancer incidence. In contrast, insights from studies of cancer-prone families as well as genome-wide association studies (GWAS) have identified both rare and common variants that lengthen telomeres as being strongly associated with cancer risk. We have hypothesized that these cancers represent a long telomere syndrome that is associated with a high penetrance of cutaneous melanoma and chronic lymphocytic leukemia. In this Review, we will synthesize the clinical and human genetic observations with data from mouse models to define the role of telomeres in cancer etiology and biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Algorithms
  • Alleles
  • Aminopeptidases / genetics
  • Animals
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Genome-Wide Association Study
  • Humans
  • Incidence
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Melanoma / genetics
  • Mice
  • Mutation*
  • Neoplasms / epidemiology
  • Neoplasms / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Serine Proteases / genetics
  • Skin Neoplasms / genetics
  • Telomerase / genetics
  • Telomere / genetics*
  • Telomere-Binding Proteins / genetics
  • Telomeric Repeat Binding Protein 2 / genetics

Substances

  • TRF2 protein, mouse
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • shelterin, human
  • TERT protein, human
  • Telomerase
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1

Supplementary concepts

  • Melanoma, Cutaneous Malignant