Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk
Por:
Rachakonda, S, Kong, H, Srinivas, N, Garcia-Casado, Z, Requena, C, Fallah, M, Heidenreich, B, Planelles, D, Traves, V, Schadendorf, D, Nagore, E and Kumar, R
Publicada:
1 nov 2018
Resumen:
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 =6x10(-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 =1x10(-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.
Filiaciones:
Rachakonda, S:
German Canc Res Ctr, Div Mol Genet Epidemiol, Neuenheumer Feld 580, D-69120 Heidelberg, Germany
Kong, H:
German Canc Res Ctr, Div Mol Genet Epidemiol, Neuenheumer Feld 580, D-69120 Heidelberg, Germany
Srinivas, N:
German Canc Res Ctr, Div Mol Genet Epidemiol, Neuenheumer Feld 580, D-69120 Heidelberg, Germany
Garcia-Casado, Z:
Inst Valenciano Oncol, Lab Mol Biol, Valencia, Spain
Requena, C:
Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain
Fallah, M:
German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany
Heidenreich, B:
German Canc Res Ctr, Div Mol Genet Epidemiol, Neuenheumer Feld 580, D-69120 Heidelberg, Germany
:
Ctr Trasfus Comunidad Valenciana, Valencia, Spain
Traves, V:
Inst Valenciano Oncol, Dept Pathol, Valencia, Spain
Schadendorf, D:
Univ Hosp Essen, Dept Dermatol, Essen, Germany
German Canc Res Ctr, German Consortium Translat Res DKTK, Heidelberg, Germany
:
Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain
Kumar, R:
German Canc Res Ctr, Div Mol Genet Epidemiol, Neuenheumer Feld 580, D-69120 Heidelberg, Germany
German Canc Res Ctr, German Consortium Translat Res DKTK, Heidelberg, Germany
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