Role of epigenetics in the etiology of germ cell cancer YVONNE G. VAN DER ZWAN 1 , HANS STOOP 1 , FERNANDO ROSSELLO 2 , STEFAN J. WHITE 2,#, LEENDERT H.J. LOOIJENGA 1,# 1 Department of Pathology, Erasmus MC – University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands, 2 Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton and 3 Centre for Reproduction and Development, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia. ABSTRACT Embryonic development is strictly controlled by functionality of genes in which the existing networks can act both on transcription and translation regulation. Germ cell cancers (GCC) are unique because of a number of characteristics. In spite of their clinical presentation, i.e., predominantly after puberty, they arise from primordial germ cells/gonocytes that have failed ap- propriate maturation to either pre-spermatogonia or oogonia. GCC mimic embryonal development to a certain extent, including capacity for totipotency.This knowledge has allowed the identification of informative diagnostic markers, including OCT3/4 (POU5F1), SOX2 and SOX17. An additional marker is the overall demethylated status of the genome. Genetic mutations in GCC are rare, which is exceptional for solid cancers. Our hypothesis is that a disturbed epigenetic regulation (through combined interaction of genetic or environmental parameters; referred to as genvironment) affect embryonic germ cell development, resulting in delayed or blocked maturation, and potentially progression to GCC. In this respect, studies of patients with Disorders of Sex Development (DSD) have increased our knowledge significantly. Genvironmental influences can lead to retention of existence of embryonic germ cells, the first step in the pathogenesis of GCC, resulting into the precursor lesions gonadoblastoma or carcinoma in situ. Identification of epigenetic alterations could lead to better understanding these processes and development of specific markers for early detection, eventually leading to development of targeted treatment. This review describes an in- teractive model related to the role of epigenetics in GCC pathogenesis, focusing on DNA methyla- tion, histone modifications, epigenetic memory and inheritance, as well as environmental factors. KEY WORDS: germ cell cancer, epigenetics, methylation, histone modifcation, environment Introduction Type II (testicular) germ cell tumors, referred to as Germ Cell Cancers (GCC), are the most common malignancy in Caucasian adolescents and young adults and their incidence is still rising (Huyghe et al., 2003, Huyghe et al., 2007). GCC arise from pri- mordial germ cells (PGC) or gonocytes and are subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Looi- jenga et al., 2011). Non-seminomas can be further categorized into embryonal carcinoma, which can differentiate into somatic lineages and extra – embryonic tissues (teratoma vs yolk sac tumor and choriocarcinoma respectively) (Looijenga et al., 2011). PGC have the intrinsic capacity for pluri/totipotency, refected in GCC, Int. J. Dev. Biol. 57: 299-308 (2013) doi: 10.1387/ijdb.130017ll www.intjdevbiol.com *Address correspondence to: Leendert H.J. Looijenga. Professor Translational Patho-Oncology , Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Building Be (Josephine Nefkens Institute), Room 432 (laboratory room 435), P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: l.looijenga@erasmusmc.nl - Tel/Fax: (31)-10-7044329/65 #Note: Both authors contributed equally to the work Final, author-corrected PDF published online: 5 June 2013. ISSN: Online 1696-3547, Print 0214-6282 © 2013 UBC Press Printed in Spain Abbreviations used in this paper: AIS, androgen insensitivity syndrome; CIS, carcinoma in situ; EC, embryonal carcinoma; ES cell, embryonic stem cell; GA, gestational age; GB, gonadoblastoma; GCC, cerm cell cancer; H3K4Me3, H3 lysine 4 tri- methylation; H3K4me1, H3 lysine 4 monomethylation; H3K27Me3, H3 lysine 27 trimethylation; H3K27Ac, H3 lysine 27 acetylase; LINE, long interspersed nucleotide element; PGC, primordial germ cell; SINE, short interspersed nucleotide element; 5mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosine. in which even the germ line can be formed in non–seminomatous tumors (Honecker et al., 2006). Regulation of pluripotency Embryonic development is controlled by highly orchestrated patterns of gene expression (both temporal and tissue specifc). It