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Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Rachakonda, Sivaramakrishna; Kong, Haiying; Srinivas, Nalini; Garcia-Casado, Zaida; Requena, Celia; Fallah, Mahdi LU ; Heidenreich, Barbara; Planelles, Dolores; Traves, Victor and Schadendorf, Dirk, et al. (2018) In Genes, Chromosomes and Cancer 57(11). p.564-572
Abstract

Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10-10 ) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly... (More)

Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10-10 ) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10-5 ) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.

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published
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Genes, Chromosomes and Cancer
volume
57
issue
11
pages
9 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85053417346
ISSN
1045-2257
DOI
10.1002/gcc.22669
language
English
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no
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d75146b3-4192-412e-b6d5-48aa8976bf5c
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2018-10-22 10:18:15
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2019-09-17 04:41:29
@article{d75146b3-4192-412e-b6d5-48aa8976bf5c,
  abstract     = {<p>Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10-10 ) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A&gt;C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10-5 ) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.</p>},
  author       = {Rachakonda, Sivaramakrishna and Kong, Haiying and Srinivas, Nalini and Garcia-Casado, Zaida and Requena, Celia and Fallah, Mahdi and Heidenreich, Barbara and Planelles, Dolores and Traves, Victor and Schadendorf, Dirk and Nagore, Eduardo and Kumar, Rajiv},
  issn         = {1045-2257},
  language     = {eng},
  number       = {11},
  pages        = {564--572},
  publisher    = {John Wiley & Sons},
  series       = {Genes, Chromosomes and Cancer},
  title        = {Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk},
  url          = {http://dx.doi.org/10.1002/gcc.22669},
  volume       = {57},
  year         = {2018},
}