A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes Karl Vandepoele1,2., Vanessa Andries1,2., Nadine Van Roy3., Katrien Staes1, Jo Vandesompele3, Genevie` ve Laureys4, Els De Smet3, Geert Berx1,2, Frank Speleman3, Frans van Roy1,2* 1 Department for Molecular Biomedical Research, VIB, Ghent, Belgium, 2 Department of Molecular Biology, Ghent University, Ghent, Belgium, 3 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 4 Department of Pediatric Hematology and Oncology, Ghent University Hospital, Ghent, Belgium Abstract The human 1p36 region is deleted in many different types of tumors, and so it probably harbors one or more tumor suppressor genes. In a Belgian neuroblastoma patient, a constitutional balanced translocation t(1;17)(p36.2;q11.2) may have led to the development of the tumor by disrupting or activating a gene. Here, we report the cloning of both translocation breakpoints and the identification of a novel gene that is disrupted by this translocation. This gene, named NBPF1 for Neuroblastoma BreakPoint Family member 1, belongs to a recently described gene family encoding highly similar proteins, the functions of which are unknown. The translocation truncates NBPF1 and gives rise to two chimeric transcripts of NBPF1 sequences fused to sequences derived from chromosome 17. On chromosome 17, the translocation disrupts one of the isoforms of ACCN1, a potential glioma tumor suppressor gene. Expression of the NBPF family in neuroblastoma cell lines is highly variable, but it is decreased in cell lines that have a deletion of chromosome 1p. More importantly, expression profiling of the NBPF1 gene showed that its expression is significantly lower in cell lines with heterozygous NBPF1 loss than in cell lines with a normal 1p chromosome. Meta-analysis of the expression of NBPF and ACCN1 in neuroblastoma tumors indicates a role for the NBPF genes and for ACCN1 in tumor aggressiveness. Additionally, DLD1 cells with inducible NBPF1 expression showed a marked decrease of clonal growth in a soft agar assay. The disruption of both NBPF1 and ACCN1 genes in this neuroblastoma patient indicates that these genes might suppress development of neuroblastoma and possibly other tumor types. Citation: Vandepoele K, Andries V, Van Roy N, Staes K, Vandesompele J, et al. (2008) A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes. PLoS ONE 3(5): e2207. doi:10.1371/journal.pone.0002207 Editor: Anja-Katrin Bielinsky, University of Minnesota, United States of America Received January 28, 2008; Accepted April 11, 2008; Published May 21, 2008 Copyright: 2008 Vandepoele et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Karl Vandepoele is supported by the Foundation against Cancer, Belgium. Vanessa Andries is supported by the Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen (IWT). Nadine Van Roy and Jo Vandesompele are postdoctoral researchers of the Fund for Scientific Research (FWO), Flanders. This work was supported by several FWO grants, by BOF and GOA grants of Ghent University, and by the Foundation against Cancer, Belgium. This text presents research results of the Belgian Program of Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s Office, Science Policy Programming and the European 6th framework programme EET pipeline. Competing Interests: The authors have declared that no competing interests exist. * E-mail: F.VanRoy@DMBR.UGent.be . These authors contributed equally to this work. Introduction Neuroblastoma, a tumor derived from pluripotent neuroblasts, is the most frequent extracranial solid malignancy of childhood. It is remarkably heterogeneous both clinically and biologically, as there is a large variation in tumor progression depending on the age of the patient at the time of diagnosis and the tumor stage [1]. Different genetic abnormalities are frequently observed in primary neuroblastoma tumors and their derivative cell lines. The most frequent aberration is the unbalanced gain of 17q, often due to translocation of the 17q segment to other chromosomes, combined with retention of two copies of the normal chromosome 17. One of the most common translocation partners for the 17q fragment is chromosome 1p, indicating that this translocation confers a selective advantage on cells by disrupting or activating certain genes [2,3]. As the translocation breakpoints are scattered on chromosomes 1 and 17, there is little evidence for a gene- specific inactivation [4]. Amplification of the proto-oncogene MYCN, which occurs in about one quarter of all neuroblastomas [1], is correlated with poor prognosis [5]. Several studies have shown a strong correlation between MYCN amplification and deletion of the short arm of chromosome 1 [6], another frequent abnormality in neuroblasto- mas. Other deletions frequently affect chromosomes 3p and 11q [1] and hint at the presence of tumor suppressor genes (TSGs) in these chromosomal regions. Previously, we described a de novo, apparently balanced, constitutional translocation t(1;17)(p36.2;q11.2) in a neuroblasto- ma patient [7]. According to Knudson’s two-hit hypothesis, constitutional deletions and translocations in patients with specific tumors are often the first indicators of the presence of TSGs. Several lines of evidence lead to the hypothesis that the 1p36 locus harbors one or more TSGs for neuroblastoma. Introduction of the short arm of chromosome 1 in the neuroblastoma cell line NGP results in a differentiated phenotype [8], providing experimental evidence for this hypothesis. Furthermore, constitutional deletions PLoS ONE | www.plosone.org 1 May 2008 | Volume 3 | Issue 5 | e2207