Imbalances of Chromosome Arm 1p in Pediatric and Adult Germ Cell Tumors Are Caused by True Allelic Loss: A Combined Comparative Genomic Hybridization and Microsatellite Analysis Susanne Zahn, 1 Sonja Sievers, 1,2 Katayoun Alemazkour, 1 Sandra Orb, 1 Dieter Harms, 3 Wolfgang A. Schulz, 4 Gabriele Calaminus, 1 Ulrich Go ¨ bel, 1 and Dominik T. Schneider 1 * 1 Clinic of Pediatric Oncology, Haematology and Immunology, Heinrich-Heine-University Dˇsseldorf,Germany 2 Max Planck Institute of Molecular Physiology, Dortmund,Germany 3 Kiel PediatricTumor Registry, Institute of Pediatric Pathology,Christian-Albrechts-University,Kiel,Germany 4 Clinic of Urology, Heinrich-Heine-University Dˇsseldorf,Germany Previous studies on childhood germ cell tumors (GCTs) report highly variable frequencies of losses at chromosome arm 1p. Since deletions at 1p portend a poor prognosis in other embryonal tumors, this study aims to clarify the question of the fre- quency of true allelic loss at 1p and whether it constitutes a prognostic parameter. We analyzed 13 GCTs from differentgo- nadal and extragonadal sites of children (4 teratomas, 9 malignant GCTs) and 18 GCTs of adolescents and adults (3 teratomas; 15 malignant GCTs) using automated microsatellite analysis with 23 polymorphic markers and chromosomal ‘‘high resolution’’ comparative genomic hybridization (HR-CGH). With this combined approach, we detected loss of heterozygosity (LOH) at 1p in 8/9 childhood malignant GCTs with concordant data from HR-CGH and microsatellite analyses. In contrast, LOH at 1p was not detected in childhood teratomas (0/4) and constituted a rare event in GCTs of adolescence and adulthood (3/18). The commonly deleted region was located at distal 1p36-pter, with a proximal boundary between the markers D1S450 and D1S2870. These data unequivocally demonstrate that deletion at 1p is common in childhood GCTs and results in allelic loss. This observation argues for the presence of a classical tumor suppressor at distal 1p. Considering the high frequency of LOH at 1p and the overall favorable prognosis of childhood GCTs, a prognostic impact of LOH at 1p in childhood GCTs appears unlikely. However, since two postpubertal tumors with LOH at 1p progressed, a prognostic relevance in this age group seems possible, warranting a prospective evaluation. V V C 2006 Wiley-Liss, Inc. INTRODUCTION Germ cell tumors (GCTs) constitute a heteroge- neous group of embryonal tumors, which originate in early embryonic development. They may develop at any age from the fetal period to adulthood and can arise both in the gonads and at extragonadal midline sites such as the coccyx, the mediastinum, and the pineal region (Calaminus et al., 2004; Schneider et al., 2004). Imprinting studies have demonstrated that the cell of origin of both gonadal and nongonadal GCTs is most probably a primitive germ cell, the primordial germ cell. Its developmen- tal potential differs according to its stage of matura- tion and pattern of genomic imprinting (van Gurp et al., 1994; Schneider et al., 2001(b); Oosterhuis et al., 2005; Sievers et al., 2005). Thus, the origin of nongonadal GCTs can be interpreted as resulting from an abnormal migration of primordial germ cells during embryogenesis. GCTs show a distinctive age distribution that separates a group of teratomas and yolk sac tumors (YST) that arise during infancy and childhood from the more diverse GCTs of adolescent and adult patients, presenting as teratomas, germinomas (seminomas, dysgerminomas), embryonal carcino- mas, choriocarcinomas, or compositions of these histological entities (Go ¨bel et al., 2000; Schneider et al., 2004; Oosterhuis et al., 2005). In addition, cystic ovarian teratomas and spermatocytic semino- mas of the elderly are considered distinct entities (Oosterhuis et al., 2005). Characteristically, the ma- jority of childhood GCTs are diagnosed at nongo- nadal sites, while in adults gonadal tumors (der- *Correspondence to: Dominik T. Schneider, M.D., Clinic of Pediatric Oncology, Hematology and Immunology, Heinrich- Heine-University, Medical Center, Moorenstr. 5, 40225 Du ¨ sseldorf, Germany. E-mail: dominik.schneider@uni-duesseldorf.de Supported by: German Cancer Aid (Deutsche Krebshilfe). Received 31 March 2006; Accepted 26 June 2006 DOI 10.1002/gcc.20363 Published online 8 August 2006 in Wiley InterScience (www.interscience.wiley.com). V V C 2006 Wiley-Liss, Inc. GENES, CHROMOSOMES & CANCER 45:995–1006 (2006)