CpG Island Methylator Phenotype Predicts Progression of Malignant Melanoma

• Published in: Clinical cancer research Vol. 15; no. 5; pp. 1801 - 1807
• Main Authors: Tanemura, Atsushi, Terando, Alicia M., Sim, Myung-Shin, van Hoesel, Anneke Q., de Maat, Michiel F.G., Morton, Donald L., Hoon, Dave S.B.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2009
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; Cells, Cultured; Child; CpG Islands - genetics; Dermatology; Dermis - cytology; Dermis - metabolism; Disease Progression; DNA Methylation; epigenetics; Female; Fibroblasts - cytology; Fibroblasts - metabolism; Genes, Tumor Suppressor; Humans; Lymphatic Metastasis; Male; malignant melanoma; Medical sciences; Melanocytes - metabolism; Melanocytes - pathology; Melanoma - genetics; Melanoma - pathology; Middle Aged; MINT; Neoplasm Staging; Pharmacology. Drug treatments; Phenotype; Prognosis; Promoter Regions, Genetic; Skin Neoplasms - genetics; Skin Neoplasms - secondary; Survival Rate; Tumors of the skin and soft tissue. Premalignant lesions; Young Adult; Phenotype; Nucleotide sequence; GC rich sequence; Malignant transformation; Malignant melanoma; Malignant tumor; Predictive factor; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1361

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, RARβ2, 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.