Molecular Analysis of Chromosome Arm 17q Gain in Neuroblastoma Isabelle Janoueix-Lerosey, 1 Dominique Penther, 1 Martine Thioux, 2 Patricia de Cre´ moux, 2 Josette Derre´, 1 Peter Ambros, 3 Philippe Vielh, 4 Jean Be´ nard, 5 Alain Aurias, 1 and Olivier Delattre 1 * 1 Laboratoire de Pathologie Mole´culaire des Cancers (Unite´ INSERM 509), Institut Curie, Paris, France 2 De´partement de Physiopathologie, Institut Curie, Paris, France 3 Children’s Cancer Research Institute, St. Anna Kinderspital, Vienna, Austria 4 De´partement d’Anatomopathologie, Institut Curie, Paris, France 5 Unite´ des Marqueurs Ge´ne´tiques due Cancer, Institut Gustave Roussy, 94800 Villejuif, France Complete or partial gain of the long arm of chromosome 17 (17q) has been shown recently by molecular cytogenetic techniques to be the most frequent chromosomal change in neuroblastoma and to be associated with adverse prognosis. Few reports, however, have focused on the precise mapping of the commonly overrepresented region. We have investigated 17q gain by the analysis of allelic imbalances at microsatellite loci dispersed along chromosome 17 in a series of 69 neuroblastomas. Allelic imbalances for at least two consecutive loci were observed in 39/59 informative cases, that is in agreement with previously reported frequencies of 17q gain. In a subset of the cases, comparative genomic hybridization analysis established the relationship between these allelic imbalances and the gain of 17q material. A partial 17q gain was observed in 9 cases, delineating a common region of 17q gain between the marker D17S787 (75 cM, 360 cR) and the telomere. In most cases, molecular results were suggestive of partial tri- or tetrasomy, whereas in 4 cases a higher copy number was documented. Our results also confirm that the presence of additional 17q material is closely associated with 1p36 deletion, MYCN amplification, and diploid or tetraploid chromosomal content. Genes Chromosomes Cancer 28:276 –284, 2000. © 2000 Wiley-Liss, Inc. INTRODUCTION Neuroblastoma is the most frequent extracranial solid tumor of childhood. This tumor, originating from cells of the neural crest, generally arises in the paraspinal sympathetic ganglia or in the adrenal medulla. The clinical behavior of neuroblastoma is extremely variable, ranging from spontaneous re- gression to metastatic progression despite intensive chemotherapy. Several types of genetic abnormal- ities, including ploidy alterations, amplification of the MYCN oncogene, and deletion of the short arm of chromosome 1 (1p), with a common region of deletion at 1p36.2–36.3, have been identified in neuroblastoma (Brodeur and Castleberry, 1997). According to these genetic alterations and to the clinical behavior, two main groups of neuroblas- toma can be clearly identified. Tumors showing a triploid nuclear DNA content, without MYCN am- plification and 1p deletion, often occur as localized tumors in children younger than one year of age (stage 1, 2, or 4S) and are associated with a good prognosis. In contrast, diploid or near-tetraploid tumors exhibiting MYCN amplification and 1p de- letion are found in older children and generally as disseminated and aggressive diseases (stage 3 or 4) and are characterized by a high mortality rate. These two groups do not account for all neuroblas- tomas, and it is likely that other more recently identified genetic alterations will enable us identify additional types of neuroblastoma and possibly to subdivide the two aforementioned groups. One of these alterations is gain of 17q material, that was initially shown by conventional cytogenet- ics to occur in 20% of neuroblastomas (Gilbert et al., 1984). More recently, the development of mo- lecular cytogenetic techniques, such as fluores- cence in situ hybridization (FISH) and comparative genomic hybridization (CGH), has shown that gain of chromosome 17 material is observed in 70 – 80% of primary neuroblastoma tumors and therefore represents the most frequent chromosomal change in this tumor (Meddeb et al., 1996; Brinkschmidt et al., 1997; Lastowska et al., 1997a; Plantaz et al., 1997; Vandesompele et al., 1998). This gain occurs either as a gain of whole chromosome 17 with no structural abnormality or as a complete or partial gain of 17q. Several cytogenetic studies have shown that 17q gains result from unbalanced trans- locations between chromosome 17 and most fre- Supported by: Institut Curie; Association pour la Recherche con- tre le Cancer (ARC); Ligue Nationale Contre le Cancer; Institut Nationale de la Sante´ et de la Recherche Me´ dicale. *Correspondence to: Olivier Delattre, Unite´ INSERM 509, Sec- tion de Recherche, Institut Curie, 26 rue d’Ulm, 75 Paris Cedex 05, France. E-mail: delattre@curie.fr Received 25 August 1999; Accepted 9 December 1999 GENES, CHROMOSOMES & CANCER 28:276 –284 (2000) © 2000 Wiley-Liss, Inc.