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Long telomeres and cancer risk: the price of cellular immortality
Emily J. McNally, … , Paz J. Luncsford, Mary Armanios
Emily J. McNally, … , Paz J. Luncsford, Mary Armanios
Published August 5, 2019
Citation Information: J Clin Invest. 2019;129(9):3474-3481. https://doi.org/10.1172/JCI120851.
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Review Series

Long telomeres and cancer risk: the price of cellular immortality

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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.

Authors

Emily J. McNally, Paz J. Luncsford, Mary Armanios

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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.

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Shared SNPs identified in GWAS near telomere genes are associated with b...
(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).

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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