Localization of a Hereditary Neuroblastoma Predisposition Gene to 16p12-p13 Matthew J. Weiss, BA, 1 Chun Guo, MS, 1 Suzanne Shusterman, MD, 1 George Hii, BS, 1 Tamar L. Mirensky, 1 Peter S. White, PhD, 1,2 Michael D. Hogarty, MD, 1,2 Timothy R. Rebbeck, PhD, 3 Dawn Teare, PhD, 4 Margrit Urbanek, PhD, 2 Garrett M. Brodeur, MD, 1,2 and John M. Maris, MD 1,2 Background. Hereditary predisposition to develop neuroblastoma segregates as an auto- somal dominant Mendelian trait. Procedure. We have performed linkage analysis on 10 families with neuroblastoma to localize a he- reditary neuroblastoma predisposition gene (HNB1). Results. A single genomic interval at chromosome bands 16p12-p13 was consistent with linkage (lod = 3.46), and identification of informative recombinants defined a 25.9-cM critical region between D16S748 and D16S3068. Loss of heterozygosity was identi- fied in 5/12 familial (42%) and 55/259 nonfa- milial (21%) neuroblastomas at multiple 16p polymorphic loci. A 12.8-cM smallest region of overlap of deletions was identified within the interval defined by linkage analysis (tel- D16S764-D16S412-cen). Conclusions. Taken together, these data suggest that HNB1 is lo- cated at 16p12-p13 and that inactivation of this gene may contribute to the pathogenesis of nonfamilial neuroblastomas. Med. Pediatr. On- col. 35:526–530, 2000. © 2000 Wiley-Liss, Inc. Key words: neuroblastoma; chromosome, human, pair 16; genes, suppressor, tumor; genetics; linkage INTRODUCTION Hereditary neuroblastoma is rare, and a family history of the disease is present in only 1–2% of newly diag- nosed cases [1–4]. Similar to retinoblastoma, patients with familial neuroblastoma are characterized by an ear- lier median age at diagnosis and a higher frequency of multifocal primary tumors. However, patients with he- reditary neuroblastoma show the same clinical heteroge- neity seen in sporadic cases, even within individual fami- lies, including cases of spontaneous regression or lethality caused by tumor progression [2,4]. As a conse- quence, the rarity of familial neuroblastoma may be ex- plained, at least in part, by both the incomplete pen- etrance and the lethality of the phenotype. As originally suggested by Knudson and Strong [1], we hypothesized that hereditary neuroblastoma occurs because of a germline mutation in one allele of a tumor- suppressor gene. In addition and by analogy with retino- blastoma, we postulated that somatically acquired muta- tions in this gene may initiate sporadic neuroblastoma tumorigenesis. We now report on the identification of a hereditary neuroblastoma predisposition locus (HNB1) at chromosome bands 16p12-p13 and provide evidence of deletion of this region during the malignant evolution of both familial and nonfamilial neuroblastomas. MATERIALS AND METHODS Families and Research Subjects Ten families with two or more individuals affected with a neuroblastic tumor were eligible for inclusion in this study. Affected patients were defined as those with biopsy-proven neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Pedigrees were ascertained through re- ferral, and a pediatric oncologist examined all affected patients. Disease was staged according to the Interna- tional Neuroblastoma Staging System [5] after review of the medical records and surgical reports. Each research subject and/or their guardian signed informed consent. The Children’s Hospital of Philadelphia Institutional Re- view Board approved this research. Samples and Genotyping Genomic DNA was extracted from whole blood, lym- phoblastoid cell lines, or bone marrow mononuclear cell pellets and from snap-frozen tumor specimens by anion 1 Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 2 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 3 Department of Genetics, University of Pennsylvania School of Medi- cine, Philadelphia, Pennsylvania 4 CRC Genetic Epidemiology Unit, Cambridge, England Contract grant sponsor: National Institutes of Health; Contract grant number: 78545; Contract grant sponsor: Children’s Hospital of Phila- delphia General Clinical Research Center; Contract grant numbers: CA78966, CA39771, M01-RR00240; Contract grant sponsors: Ameri- can Society of Clinical Oncology, American Cancer Society. *Correspondence to: Dr. John M. Maris, Division of Oncology, Chil- dren’s Hospital of Philadelphia, Abramson Pediatric Research Center 902A, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. E-mail: maris@email.chop.edu Medical and Pediatric Oncology 35:526–530 (2000) © 2000 Wiley-Liss, Inc.