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

Long telomeres and cancer risk: the price of cellular immortality

Emily J McNally  1   2 , Paz J Luncsford  1   2 , Mary Armanios  1   2   3   4
Affiliations
Review

Long telomeres and cancer risk: the price of cellular immortality

Emily J McNally et al. J Clin Invest. .

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.

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Conflict of interest statement

Conflict of interest: EJM is currently employed by and has stock options in SQZ Biotech, a cell therapy company.

Figures

Figure 1
Figure 1. Schematic of mutant telomerase and telomere genes in Mendelian short and long telomere syndromes and model for TPP1 allele–specific effects on telomere length.
(A) Components with known mutations are shown in color, and their telomere function is indicated above each group. Thirteen genes have been identified, with the short telomere syndrome associations marked by a subscript S. Four genes are associated with long telomere syndrome phenotypes and are marked by a superscript L. Adapted with permission from Current Opinion in Genetics & Development (13). (B) The left panel shows the state of telomere length maintenance normally. The middle panel shows how in-frame deletions in the TEL patch interfere with TERT recruitment and processivity, provoking telomere shortening. The right panel shows a model for how cancer-associated mutations may promote telomere maintenance in cancer-prone families. TPP1 deletions or missense mutations in the POT1-interating domain are predicted to affect POT1’s telomere-binding capacity, allowing TERT to elongate more efficiently. The latter is hypothesized to have a net effect of telomere lengthening and/or telomere maintenance.
Figure 2
Figure 2. Shared SNPs identified in GWAS near telomere genes are associated with both telomere length and disease risk, but the directionality of the effect is allele-dependent.
(A) intersection of shared SNPs across GWAS for leukocyte telomere length, lung adenocarcinoma and idiopathic pulmonary fibrosis. The shared SNPs fall near telomere maintenance genes. The alleles for each SNP have differential effects on telomere length with the effect size shown on base pairs. rs2736100 is in intron 2 of TERT. rs755017 is 140 kb downstream of the RTEL1 transcription start site in exon 2. rs7675998 falls 40 kb upstream of the NAF1 transcription start site. (B) Schematic forest plot shows the odds ratio of disease risk with short and long telomere SNPs such as those shown in the table in A. Data in B are adapted with permission from JAMA Oncology (88).
Figure 3
Figure 3. Long telomeres promote cancer-related mortality in mice and proposed mechanism for long-telomere melanomagenesis.
(A) Survival curve summarizing data from mouse models examining the role of telomerase and telomere length in cancer-related survival. It shows a survival advantage for short-telomere mice in a model of Myc-induced lymphoma, according to Feldser et al. (adapted with permission from Cancer Cell; ref. 91). (B) Schematic model for how long-telomere melanoma cells prone to environmentally induced DNA damage may have an advantage in cancer progression.
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