Melanoma Is Distinguished by Loss of 5-Hydroxymethylcytosine

Histologic similarities between benign and malignant melanocytic lesions can hinder diagnosis and efforts to predict clinical outcome. Cancerous cells can frequently be distinguished from benign cells by genome-wide abnormalities in epigenetic marks, such as 5-hydroxymethylcytosine (5-hmC), which has been shown to be globally reduced in tumor cells. This finding, together with the observation that gain-of-function isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations that block the conversion of 5-methylcytosine to 5-hmC occur in 10% of melanomas, led Lian and colleagues to hypothesize that 5-hmC levels might distinguish malignant melanoma from benign melanocytic nevi. Indeed, mature melanocytes and benign nevi had high nuclear levels of 5-hmC, whereas 5-hmC was partially or completely lost in most primary or metastatic melanomas. Furthermore, 5-hmC loss was correlated with a higher tumor stage, was associated with a worse prognosis, and was enriched at genes associated with melanogenesis and cancer-related pathways, suggesting that a progressive change in the 5-hmC landscape contributes to tumor formation. To determine how 5-hmC depletion might occur, the authors evaluated the expression levels of the ten-eleven translocation (TET) family of DNA hydroxylases that directly generate 5-hmC as well as IDH1 and IDH2, which normally generate the key cofactor required by TET enzymes. Compared with nevi, IDH2 and all 3 TET genes (TET1-3) were significantly downregulated in melanoma patient samples, implicating downregulation of enzymes required for the generation of 5-hmC in melanomagenesis. Consistent with this possibility, IDH2 overexpression in a zebrafish melanoma model increased 5-hmC levels and delayed tumor formation, and TET2 overexpression in human melanoma cells reestablished the 5-hmC landscape and slowed xenograft tumor growth. Collectively, these findings suggest that 5-hmC loss drives melanoma progression and that restoration of genome-wide 5-hmC levels may suppress melanoma growth.

Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012;150:1135–46.