title: Genetic and Epigenetic Alterations of TERT Are Associated with Inferior Outcome in Adolescent and Young Adult Patients with Melanoma.
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.
authors.affiliation: Department of Pediatric Hematology/Oncology, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Brittani
authors.initials: B
authors.lastname: Seynnaeve
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Seungjae
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Borah
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis Tennessee 38105, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pappo
authors.affiliation: Department of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.|Department of Oncology, St. Jude Children's Research Hospital, Memphis Tennessee 38105, USA.
authors.forename: Armita
authors.initials: A
authors.lastname: Bahrami
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality*; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics*; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C509186:TERT protein, human; D019098:Telomerase