Identification of novel imprinted tumor suppressor gene on 14q for human renal mil carcinoma

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A common deletion at chromosomal arm 14q32 in human renal cell carcinoma (RCC) prompted us to explore a tumor suppressor gene (TSG) in this region. We report that imprinted DLK1 at 14q32, a regulator of adipocyte differentiation, is a candidate TSG in RCCs. Expression of DLK1 were diminished in both early and advanced stages of RCCs while normal kidney tissues expressed DLKI. Reintroduction of DLKI into DLK1-null RCC cell lines markedly increased anchorage-independent cell death, anoikis, and suppressed tumor growth in nude mice. Furthermore, we show that gain of methylation upstream of GTL2, a reciprocal imprinted gene for DLK1, is a critical epigenetic alteration for the inactivation of DLK1 in RCCs. The imprinted DLKI/GTL2 domain at 14q32 shares structural and epigenetic similarities with the IGF2/H19 domain at 11p15.5. Gain of methylation upstream of the untranslated H19 leads to pathological biallelic expression of IGF2 in Wilms tumors. In contrast, the present data have shown that gain of methylation upstream of the untranslated GTL2 leads to pathological down regulation of DLK1 in RCCs.