CpG Island Methylator Phenotype Predicts Progression of Malignant Melanoma

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, RARh2, 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 theTRGsWIF1,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 MINT31is 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.

Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells

“…Decreased SOCS gene expression due to promoter methylation has been observed in advanced human cancers including melanoma [1][2][3][4][5][6][7]. In agreement with a proposed role in tumor suppression, SOCS1-deficient mice show myeloproliferative disorders and lymphomas [8][9][10].…”

“…Human tumor cells have developed mechanisms to prevent SOCS1 expression, which endows them with a greater capacity for proliferation and resistance to apoptosis [13]. Loss of SOCS1 results critical for enhanced invasion and angiogenesis of melanoma cells [12], and SOCS1 hypermethylation predicts progression of malignant melanoma [7]. Here we used several SOCS1-negative human melanoma cell lines (BLM, MeWo, HT-1080 and UACC-257) to show that SOCS1 expression regulates their proliferation both in vitro and in vivo.…”

Epigenetic regulation in human melanoma: past and future

“…This suggests that RASSF1A might be used as a marker of progression and prognosis in malignant melanoma. 26 The role of this gene as a human tumor suppressor, and how it contributes to melanoma development, have been elucidated. RASSF1A upregulates ASK1, which in turn activates p38 MAPK.…”

Lymphovascular invasion of colorectal cancer is correlated to SPARC expression in the tumor stromal microenvironment

“…24,25 Recent studies by our group and others on CRC have focused on tumor-related genes and epigenetic regulation by methylation status of specific CpG island sites in the promoter region. [26][27][28][29] However, these studies have not included stromal cells in the tumor microenvironment. Tumor microenvironment may provide the necessary conditions for tumor migration and invasion by fostering adaptation to the effects of tumor-associated epigenetic changes.…”