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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Sivaramakrishna Rachakonda
  • Haiying Kong
  • Nalini Srinivas
  • Zaida Garcia-Casado
  • Celia Requena
  • Mahdi Fallah
  • Barbara Heidenreich
  • Dolores Planelles
  • Victor Traves
  • Dirk Schadendorf
  • Eduardo Nagore
  • Rajiv Kumar
External organisations
  • German Cancer Research Centre
  • Valencia Oncology Institute Foundation
  • University Hospital Essen
Original languageEnglish
Pages (from-to)564-572
Number of pages9
JournalGenes, Chromosomes and Cancer
Volume57
Issue number11
Publication statusPublished - 2018 Nov
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes