Distinctive epigenetic phenotype of cancer testis antigen genes among seminomatous and nonseminomatous testicular germ-cell tumors

Testicular germ-cell tumors (TGCTs) are pluripotent and display protean histology from the germ-cell stage until embryonal and somatic-cell differentiation. These properties make TGCT a fascinating model for studying germ-cell development and gametogenesis. Methylation patterns specific to cell type (stem cells, germ cells, and somatic tissues) occur throughout the normal development of mice. To shed light on the epigenetic phenotypes among histological subtypes of TGCTs, we investigated the methylation and expression of several cancer testis antigen (CTA) genes (MAGEA1, MAGEA3, and SYCP1) in TGCTs. In the current study, we showed that the 5' ends of MAGEA1 and MAGEA3 on the X chromosome are unmethylated in seminomatous TGCTs, regardless of whether MAGEA1 and MAGEA3 are expressed and are methylated in nonseminomatous TGCTs when expression is absent. These distinctive epigenetic phenotypes of MAGEA1 and MAGEA3 also were observed in pure seminomas and in the seminomatous elements of mixed-type TGCTs. In contrast, the 5' end of SYCP1, on chromosome 1, remained predominantly unmethylated, regardless of expression, in both seminomatous and nonseminomatous TGCTs. This pattern of transcriptional regulation of SYCP1 is similar to that observed for XIST in TGCTs. On the basis of the epigenetic phenotypes of CTA genes, we concluded that, first, consistent unmethylated DNA profiles in seminomatous TGCTs imply that methylation may not be the primary control mechanism of programmed gene expression in seminomatous TGCTs, and, second, that nonseminomatous TGCTs might be midway between seminomatous TGCTs and somatic tissues because gene expression in nonseminomatous TGCTs is regulated by methylation in some genes (MAGEA1 and MAGEA3) but not others (SYCP1 and XIST).