RASSF10 Promoter Hypermethylation Is Frequent in Malignant Melanoma of the Skin but Uncommon in Nevus Cell Nevi

Abstract

The Ras association domain family (RASSF) consists of several tumor suppressor genes, which are frequently silenced in human cancers. We analyzed the epigenetic inactivation of RASSF2 and RASSF10 in malignant melanoma (MM) of the skin, including 5 MM cell lines, 28 primary MM, 33 metastases of MM, 47 nevus cell nevi (NCN), and 22 control tissues. The RASSF2 promoter was epigenetically downregulated in two MM cell lines only, but not in any of the investigated tumor samples. In contrast, hypermethylation of the RASSF10 promoter was found in all investigated cell lines, 19/28 (68%) of the primary MM and 30/33 (91%) of the MM metastases, 2/18 (11%) of the dysplastic NCN, and 0/29 (0%) of the non-dysplastic NCN (difference between MM and all nevi, P<0.001). RASSF10 promoter hypermethylation correlated with a reduced RASSF10 mRNA expression in 3/4 MM cell lines, and treatment with a DNA methylation inhibitor reactivated RASSF10 transcription. Furthermore, immunohistological RASSF10 expression corresponds negatively to its promoter methylation state. In summary, RASSF10 proved to be a characteristically epigenetically silenced tumor suppressor in melanomagenesis, and analysis of RASSF10 methylation status represents a new candidate tool to assist in discrimination between MM and NCN.

Aberrant Promoter Hypermethylation of RASSF Family Members in Merkel Cell Carcinoma

“…We and others showed promoter hypermethylation of RASSF2 [18,19,20], RASSF5A [21], RASSF5C [22] and RASSF10 [23,24,25,26,27,28]. For the most prominent family member RASSF1A we already reported strong promoter hypermethylation in MCC [7], which was in accordance with its status of a very well characterized epigenetically inactivated tumor suppressor [17].…”

Novel DNA methylation markers with potential prognostic relevance in advanced malignant melanoma identified using COBRA assays

“…Epigenetic inactivation of tumor suppressor genes has been implicated in tumorigenesis and progression of a variety of different malignancies [9][10][11], and recent studies are beginning to show the role of epigenetic events in cutaneous melanoma.…”

RASSF tumor suppressor gene family: Biological functions and regulation

“…To date, 68% of malignant melanoma patient samples tested harbor epigenetically silenced RASSF10 [150]. In addition, RASSF10 promoter methylation has been observed in prostate cancer patients as well as up to 88% of paediatric leukemias, 50% of chronic lymphocytic leukemia, 66% of thyroid cancers, and 68% of melanoma (please see Table 2 for the complete list and references).…”