Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma

Autors de IIS La Fe

• Blanca De Unamuno Bustos

  Autor

• Rosa María Murria Estal

  Autor

• Gema Pérez Simó

  Autor

• Javier Simarro Farinos

  Autor

• Conrad Pujol Marco

  Autor

• Miguel Ángel Navarro Mira

  Autor

• Rosa Ballester Sanchez

  Autor

• Margarita Mercedes Llavador Ros

  Autor

• Sarai Palanca Suela

  Autor

• 

  Rafael Botella Estrada

  Autor

Autors aliens a IIS La Fe

• Alegre de Miquel, V
• Sabater Marco, V

Grups d'Investigació

• Dermatología y Regeneración Tisular

  

  Leader

  Rafael Botella Estrada

• Investigación Clínica y Traslacional en Cáncer

  

  Leader

  José Gómez Codina

Abstract

BackgroundPromoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. ObjectivesThis is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival. Materials and methodsDNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method. ResultsIn the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS. ConclusionsAberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice. What's already known about this topic? Epigenetic aberrations have recently been implicated in the development and progression of many human cancers. Regarding melanoma, over 100 genes have been identified to be aberrantly hypermethylated. What does this study add? Aberrant methylation of tumour suppressor gene promoters is associated with aggressive clinicopathological features and poorer melanoma survival. What is the translational message? DNA methylation may represent a potential prognostic biomarker for the management of patients with melanoma in routine practice. Linked Comment:van Doorn. Br J Dermatol 2018; 179:250-251. Respond to this article

Keywords

• MALIGNANT-MELANOMA; PROMOTER METHYLATION; PROGNOSTIC-FACTOR; PROGRESSION; GENE; TUMORS; PTEN