Methylation levels of the "long interspersed nucleotide element-1" repetitive sequences predict survival of melanoma patients

J Transl Med. 2011 May 26:9:78. doi: 10.1186/1479-5876-9-78.

Abstract

Background: The prognosis of cutaneous melanoma (CM) differs for patients with identical clinico-pathological stage, and no molecular markers discriminating the prognosis of stage III individuals have been established. Genome-wide alterations in DNA methylation are a common event in cancer. This study aimed to define the prognostic value of genomic DNA methylation levels in stage III CM patients.

Methods: Overall level of genomic DNA methylation was measured using bisulfite pyrosequencing at three CpG sites (CpG1, CpG2, CpG3) of the Long Interspersed Nucleotide Element-1 (LINE-1) sequences in short-term CM cultures from 42 stage IIIC patients. The impact of LINE-1 methylation on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analysis.

Results: Hypomethylation (i.e., methylation below median) at CpG2 and CpG3 sites significantly associated with improved prognosis of CM, CpG3 showing the strongest association. Patients with hypomethylated CpG3 had increased OS (P = 0.01, log-rank = 6.39) by Kaplan-Meyer analysis. Median OS of patients with hypomethylated or hypermethylated CpG3 were 31.9 and 11.5 months, respectively. The 5 year OS for patients with hypomethylated CpG3 was 48% compared to 7% for patients with hypermethylated sequences. Among the variables examined by Cox regression analysis, LINE-1 methylation at CpG2 and CpG3 was the only predictor of OS (Hazard Ratio = 2.63, for hypermethylated CpG3; 95% Confidence Interval: 1.21-5.69; P = 0.01).

Conclusion: LINE-1 methylation is identified as a molecular marker of prognosis for CM patients in stage IIIC. Evaluation of LINE-1 promises to represent a key tool for driving the most appropriate clinical management of stage III CM patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • DNA Methylation / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Long Interspersed Nucleotide Elements / genetics*
  • Male
  • Melanoma / diagnosis
  • Melanoma / genetics*
  • Melanoma / pathology
  • Middle Aged
  • Molecular Sequence Data
  • Neoplasm Staging
  • Prognosis
  • Proportional Hazards Models
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sequence Analysis, DNA
  • Skin Neoplasms / diagnosis
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology

Substances

  • RNA, Messenger