Carcinoma in situ testis displays permissive chromatin modifications similar to immature foetal germ cells

• Published in: British journal of cancer Vol. 103; no. 8; pp. 1269 - 1276
• Main Authors: Almstrup, K, Nielsen, J E, Mlynarska, O, Jansen, M T, Jørgensen, A, Skakkebæk, N E, Rajpert-De Meyts, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2010; Nature Publishing Group
• Subjects: 631/136/532/1519; 631/45/612/100/102; 692/699/67/1836; Adult; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma in Situ - metabolism; Carcinoma in Situ - pathology; Cell Proliferation; Chromatin - metabolism; Chromatin Assembly and Disassembly - physiology; DNA Methylation; Drug Resistance; Epidemiology; Epigenesis, Genetic - physiology; Epigenetics; Fetus - metabolism; Gene expression; Genetics and Genomics; Genomes; Germ Cells - metabolism; Gestational Age; Gynecology. Andrology. Obstetrics; Histones - metabolism; Humans; Male; Male genital diseases; Medical research; Medical sciences; Molecular Medicine; Neoplasms, Germ Cell and Embryonal - metabolism; Oncology; Protein Processing, Post-Translational; Puberty - metabolism; RNA polymerase; Testicular cancer; Testicular Neoplasms - metabolism; Testicular Neoplasms - pathology; Transcriptional Activation; Tumors; Denmark; testicular cancer; chromatin; carcinoma; foetal germ cells; epigenetics; Modification; Chromatin; Carcinoma in situ; Malignant tumor; Testicle; Male genital system; Cancerology; Epigenetics; Immaturity; Male genital diseases; Testicular diseases; Testicle cancer; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605880

Background: The majority of testicular germ cell cancers develop through a pre-invasive carcinoma in situ (CIS) stage. The CIS cell is a neoplastic counterpart of foetal germ cells. During their development, foetal germ cells undergo extensive and essential epigenetic modifications, but little is known about epigenetic patterns in CIS cells. Methods: Immunohistochemistry was used to investigate epigenetic patterns in CIS, germ cell tumours, normal adult and foetal testicular tissue. Results: CIS cells show low levels of DNA methylation and repressive histone modifications H3K9me2 and H3K27me3, but high levels of H3K9 acetylation, H3K4 methylation and H2A.Z, which all are associated with an activated and accessible chromatin structure. Collectively this renders a permissive chromatin structure and in accordance high levels of RNA polymerase II activity and proliferation (Ki-67 and mitotic index) is observed in CIS cells. Epigenetic patterns similar to that of CIS cells were observed in human gonocytes present within sex cords in foetal testes but correspond to migrating primordial germ cell in mice. Development of overt tumours involves epigenetic repression of the chromatin. Conclusion: CIS cells have a permissive and foetal-like chromatin structure, which is associated with a high transcriptional and proliferative activity, likely empowering neoplastic transformation. Developmental epigenetic cues in foetal germ cells are substantially different between humans and mice.