Extensive genomic demethylation - a histological hallmark of germinomatous tumors

Abstract

1606

DNA methylation is a major epigenetic modification of the genome that regulates crucial aspects of its function. Genomic methylation patterns in somatic differentiated cells are generally stable and heritable. However, in mammals there are at least two developmental periods-in germ cells and in preimplantation embryos-in which methylation patterns are reprogrammed genome wide, generating cells with a broad developmental potential. Methylation reprogramming in the germ line. Primordial germ cells (PGCs) become demethylated early in development. Remethylation begins in prospermatogonia on E16 in male germ cells, and after birth in growing oocytes. Reprogramming is likely to have a crucial role in establishing nuclear totipotency in normal development, and in the erasure of acquired epigenetic information. Methylation occurs predominantly at the symmetrical dinucleotide CpG. In this study we have stained normal somatic tissues as well as different types of germ cell tumors including 15 germinomas of the CNS, 10 ovarian dysgerminomas and 5 seminomas of the testis with a monoclonal antibody against methylated cytidine residues. While normal somatic tissues were ubiquitously and strongly labelled with this antibody reflecting methylated nuclear DNA all germ cell tumors were negative. In a mixed germ cell tumor only the germinomatous tumor cells had unstained nuclei whereas the teratomatous component was positive. Infiltrating lymphocytes and endothelial cells in the tumors showed nuclear reactivity. Germ cells of a 13 - 14 weeks old female fetus also displayed a demethylated chromatin. The data suggest that germinomatous tumor cells display a demethylated nuclear DNA similar to primordial germ cells in early development. Demethylated nuclear DNA can easily be visualized by immunohistochemistry and represents a novel marker for germinomatous tumors.