Abstract
BackgroundOriginating from Primordial Germ Cells/gonocytes and developing via a precursor lesion called Carcinoma In Situ (CIS), Germ Cell Cancers (GCC) are the most common cancer in young men, subdivided in seminoma (SE) and non-seminoma (NS). During physiological germ cell formation/maturation, epigenetic processes guard homeostasis by regulating the accessibility of the DNA to facilitate transcription. Epigenetic deregulation through genetic and environmental parameters (i.e. genvironment) could disrupt embryonic germ cell development, resulting in delayed or blocked maturation. This potentially facilitates the formation of CIS and progression to invasive GCC. Therefore, determining the epigenetic and functional genomic landscape in GCC cell lines could provide insight into the pathophysiology and etiology of GCC and provide guidance for targeted functional experiments.ResultsThis study aims at identifying epigenetic footprints in SE and EC cell lines in genome-wide profiles by studying the interaction between gene expression, DNA CpG methylation and histone modifications, and their function in the pathophysiology and etiology of GCC. Two well characterized GCC-derived cell lines were compared, one representative for SE (TCam-2) and the other for EC (NCCIT). Data were acquired using the Illumina HumanHT-12-v4 (gene expression) and HumanMethylation450 BeadChip (methylation) microarrays as well as ChIP-sequencing (activating histone modifications (H3K4me3, H3K27ac)). Results indicate known germ cell markers not only to be differentiating between SE and NS at the expression level, but also in the epigenetic landscape.ConclusionThe overall similarity between TCam-2/NCCIT support an erased embryonic germ cell arrested in early gonadal development as common cell of origin although the exact developmental stage from which the tumor cells are derived might differ. Indeed, subtle difference in the (integrated) epigenetic and expression profiles indicate TCam-2 to exhibit a more germ cell-like profile, whereas NCCIT shows a more pluripotent phenotype. The results provide insight into the functional genome in GCC cell lines.
Highlights
Type II germ cell tumors, here referred to as Germ Cell Cancers (GCC), are the most common malignancy in Caucasian adolescents and young adults, and their incidence is still rising [1,2,3]
To investigate epigenetic characteristics of SE and EC and their relationship to gene expression, genome-wide histone modification and DNA methylation patterns were investigated in the cell lines TCam-2 (SE) and NCCIT (EC), and matched to gene expression profiles
We previously showed that active chromatin modification patterns for SOX17 and SOX2 in the cell lines TCam2 and NCCIT match the expected pattern, based on gene and protein expression and histological constitution (SOX17 active in TCam-2, SOX2 active in NCCIT) [25]
Summary
Type II (testicular) germ cell tumors, here referred to as Germ Cell Cancers (GCC), are the most common malignancy in Caucasian adolescents and young adults, and their incidence is still rising [1,2,3]. GCC originate from primordial germ cells or gonocytes, and are subdivided into seminomas (SE) and nonseminomas (NS), with carcinoma in situ (CIS) of the testis as their common precursor lesion [1], known as Intratubular Germ Cell Neoplasia Unclassified (IGCNU) [3]. Originating from Primordial Germ Cells/gonocytes and developing via a precursor lesion called Carcinoma In Situ (CIS), Germ Cell Cancers (GCC) are the most common cancer in young men, subdivided in seminoma (SE) and nonseminoma (NS). Epigenetic deregulation through genetic and environmental parameters (i.e. genvironment) could disrupt embryonic germ cell development, resulting in delayed or blocked maturation. This potentially facilitates the formation of CIS and progression to invasive GCC. Determining the epigenetic and functional genomic landscape in GCC cell lines could provide insight into the pathophysiology and etiology of GCC and provide guidance for targeted functional experiments
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