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LINE-1 hypomethylation and mutational status in cutaneous melanomas
  1. Dimitrius T Pramio1,
  2. Paula C Pennacchi2,
  3. Silvya S Maria-Engler2,
  4. Antônio H J F M Campos3,
  5. João P Duprat4,
  6. Dirce M Carraro1,
  7. Ana C V Krepischi5
  1. 1International Research Center, AC Camargo Cancer Center, São Paulo, Brazil
  2. 2Clinical Chemistry and Toxicology Department, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
  3. 3Department of Anatomic Pathology, AC Camargo Cancer Center, São Paulo, Brazil
  4. 4Skin Cancer Department, AC Camargo Cancer Center, São Paulo, Brazil
  5. 5Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  1. Correspondence to Dr Ana C V Krepischi, Department of Genetics and Evolutionary Biology, University of São Paulo, Institute of Biosciences, Rua do Matão, 277—Cidade Universitária—Butantã—CEP 05508-090, São Paulo, Brazil; ana.krepischi{at}


Epigenetic dysregulation is an important emerging hallmark of cutaneous melanoma development. The global loss of DNA methylation in gene-poor regions and transposable DNA elements of cancer cells contributes to increased genomic instability. Long interspersed element-1 (LINE-1) sequences are the most abundant repetitive sequence of the genome and can be evaluated as a surrogate marker of the global level of DNA methylation. In this work, LINE-1 methylation levels were evaluated in cutaneous melanomas and normal melanocyte primary cell cultures to investigate their possible association with both distinct clinicopathological characteristics and tumor mutational profile. A set of driver mutations frequently identified in cutaneous melanoma was assessed by sequencing (actionable mutations in BRAF, NRAS, and KIT genes, and mutations affecting the TERT promoter) or multiplex ligation-dependent probe amplification (MLPA) (CDKN2A deletions). Pyrosequencing was performed to investigate the methylation level of LINE-1 and CDKN2A promoter sequences. The qualitative analysis showed a trend toward an association between LINE-1 hypomethylation and CDKN2A inactivation (p=0.05). In a quantitative approach, primary tumors, mainly the thicker ones (>4 mm), exhibited a trend toward LINE-1 hypomethylation when compared with control melanocytes. To date, this is the first study reporting in cutaneous melanomas a possible link between the dysregulation of LINE-1 methylation and the presence of driver mutations.

  • Biomedical Research
  • Cancer
  • Genotype
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