title: TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms.
abstract: Spitzoid neoplasms constitute a morphologically distinct category of melanocytic tumors, encompassing Spitz nevus (benign), atypical Spitz tumor (intermediate malignant potential), and spitzoid melanoma (fully malignant). Currently, no reliable histopathological criteria or molecular marker is known to distinguish borderline from overtly malignant neoplasms. Because TERT promoter (TERT-p) mutations are common in inherently aggressive cutaneous conventional melanoma, we sought to evaluate their prognostic significance in spitzoid neoplasms. We analyzed tumors labeled as atypical Spitz tumor or spitzoid melanoma from 56 patients with available follow-up data for the association of TERT-p mutations, biallelic CDKN2A deletion, biallelic PTEN deletion, kinase fusions, BRAF/NRAS mutations, nodal status, and histopathological parameters with risk of hematogenous metastasis. Four patients died of disseminated disease and 52 patients were alive and disease free without extranodal metastasis (median follow-up, 32.5 months). We found TERT-p mutations in samples from the 4 patients who developed hematogenous metastasis but in none of tumors from patients who had favorable outcomes. Presence of TERT-p mutations was the most significant predictor of haematogenous dissemination (P < 0.0001) among variables analyzed. We conclude that TERT-p mutations identify a clinically high-risk subset of patients with spitzoid tumors. Application of TERT-p mutational assays for risk stratification in the clinic requires large-scale validation.
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: Département de BioPathologie, Institut Curie, 26 rue d'Ulm, 75248, Paris cedex 05, France.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Barnhill
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
authors.forename: James
authors.initials: J
authors.lastname: Dalton
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
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 Pathology, 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; D002675:Child, Preschool; D005260:Female; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D019098:Telomerase / Q000235:genetics*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D051059:PTEN Phosphohydrolase