Abstract
Progression of melanoma to distant sites in adolescents and young adults (AYAs) is not reliably predicted by clinicopathologic criteria. TERT promoter mutations when combined with BRAF/NRAS mutations correlate with adverse outcome in adult melanoma. To determine the prognostic value of TERT alterations in AYA melanoma, we investigated the association of TERT promoter mutations, as well as promoter methylation, an epigenetic alteration also linked to TERT upregulation, with TERT mRNA expression and outcome using a well-characterized cohort of 27 patients with melanoma (ages 8–25, mean 20). TERT mRNA expression levels were significantly higher in tumors harboring TERT promoter mutation and/or hypermethylation than those without either aberration (P = 0.046). TERT promoter mutations alone did not predict adverse outcomes (P = 0.50), but the presence of TERT promoter methylation, alone or concurrent with promoter mutations, correlated with reduced recurrence-free survival (P = 0.001). These data suggest that genetic and epigenetic alterations of TERT are associated with TERT upregulation and may predict clinical outcomes in AYA melanoma. A more exhaustive understanding of the different molecular mechanisms leading to increased TERT expression may guide development of prognostic assays to stratify AYA melanoma patients according to clinical risk.
Highlights
In contrast to the static situation in AYA, advances in understanding the genomics of adult melanoma have changed the treatment paradigm for advanced staged melanoma in adults
Given the association of TERT promoter mutations with adverse outcome in adult melanoma patients[22], we investigated the prognostic value of these mutations, as well as promoter hypermethylation−an epigenetic alteration linked to TERT upregulation in a subset of melanomas[29], using 28 tissue specimens from a well-annotated cohort of 27 AYA melanomas at the University of Pittsburgh
MassARRAY revealed that 8 of 19 (42%) cases of conventional melanomas and none of the nevoid or spitzoid melanomas harbored hypermethylated CpG dinucleotides in the Upstream of the Transcription Start Site (UTSS) region of the TERT promoter (Supplementary Table 2); hypermethylation in this region has been shown to correlate with increased TERT expression and poorer patient outcome in a number of different cancers[33]
Summary
In contrast to the static situation in AYA, advances in understanding the genomics of adult melanoma have changed the treatment paradigm for advanced staged melanoma in adults. Given the association of TERT promoter mutations with adverse outcome in adult melanoma patients[22], we investigated the prognostic value of these mutations, as well as promoter hypermethylation−an epigenetic alteration linked to TERT upregulation in a subset of melanomas[29], using 28 tissue specimens from a well-annotated cohort of 27 AYA melanomas at the University of Pittsburgh. This cohort included cases of conventional melanoma (n = 20), nevoid melanoma (n = 2), and spitzoid melanoma (n = 6). The prognostic value of these for recurrence-free survival and overall survival was calculated
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