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Comparative Study
. 2009 Mar 1;15(5):1801-7.
doi: 10.1158/1078-0432.CCR-08-1361. Epub 2009 Feb 17.

CpG island methylator phenotype predicts progression of malignant melanoma

Atsushi Tanemura  1 , Alicia M Terando, Myung-Shin Sim, Anneke Q van Hoesel, Michiel F G de Maat, Donald L Morton, Dave S B Hoon
Affiliations
Comparative Study

CpG island methylator phenotype predicts progression of malignant melanoma

Atsushi Tanemura et al. Clin Cancer Res. .

Abstract

Purpose: The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression.

Experimental design: The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARbeta2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n=122) was assessed.

Results: Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma.

Conclusions: These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.

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Figures

Fig. 1
Fig. 1
Methylation of MINT loci increases with advancing AJCC stage. MINT17 (A) and MINT31 (B) methylation indices for each tumor specimen stratified by AJCC stage. Columns, mean for grouping of each stage.
Fig. 2
Fig. 2
Improved disease-free and overall survival for AJCC stage III patients with MINT31 methylation. Kaplan-Meier curves for disease-free survival (A) and overall survival (B) in stage III patients. Log-rank test confirmed better disease-free survival (P = 0.047) and overall survival (P = 0.013) for patients with tumor samples with MINT31 methylation.
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