Heterogeneity of chromatin modifications in testicular spermatocytic seminoma point toward an epigenetically unstable phenotype

Abstract

Testicular spermatocytic seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a series of 36 SS samples. We assessed by immunohistochemistry tumor DNA methylation levels, the expression of methyltransferases DNMT3A, DNMT3B and DNMT3L as well as levels of histone modifications H3K9me2, H3K27me3, H3K4me1, H3K4me2/3, H3K9ac, and H2A.Z. We did not identify any epigenetic marks that matched the pattern of the supposed cell-of-origin, the spermatogonia, and found no correlation between specific marks and the size of the SS cells. The emerging epigenetic picture of SS is a heterogeneous "salt-and-pepper"-like pattern, with neighboring cells displaying very variable levels of epigenetic marks. We conclude that SS cells display apparent epigenetic heterogeneity and instability, with loss of the organized manner typical for normal germ cell maturation in the adult testis, likely due to the lack of regulatory signals from the absent somatic cell niche.