title: Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients.
abstract: The NBN (NBS1) gene belongs to a group of double-strand break repair genes. Mutations in any of these genes cause genome instability syndromes and contribute to carcinogenesis. NBN gene mutations cause increased tumor risk in Nijmegen breakage syndrome (NBS) homozygotes as well as in NBN heterozygotes. NBS patients develop different types of malignancies; among solid tumors, medulloblastoma (MB), an embryonal tumor of the cerebellum, has been reported most frequently. The majority of medulloblastomas occur sporadically, some of them manifest within familial cancer syndromes. Several signaling pathways are known to be engaged in hereditary and sporadic MB. The aim of our study was to identify mutations in selected exons of the NBN gene and to determine the frequency of the most common NBN gene mutations in pediatric patients with different types of medulloblastoma. We screened a total of 104 patients with MB and identified 7 heterozygous carriers (6.7%) of two different germ-line mutations of NBN gene; all of them had classic MB. Our results indicate that heterozygous carriers of the germ-line NBN gene mutations (c.511A>G and c.657_661del5) may exhibit increased susceptibility to developing MB. The risk of medulloblastoma is estimated to be 3.0 (for c.511A>G) and 4.86 (for c.657_661del5) times higher than in the general Polish population (p<0.05). These results suggest that heterozygous NBN germ-line mutations may contribute to the etiology of medulloblastoma.
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Ciara
authors.forename: Dorota
authors.initials: D
authors.lastname: Piekutowska-Abramczuk
authors.forename: Ewa
authors.initials: E
authors.lastname: Popowska
authors.forename: Wiesława
authors.initials: W
authors.lastname: Grajkowska
authors.forename: Sławomir
authors.initials: S
authors.lastname: Barszcz
authors.forename: Danuta
authors.initials: D
authors.lastname: Perek
authors.forename: Bożenna
authors.initials: B
authors.lastname: Dembowska-Bagińska
authors.forename: Marta
authors.initials: M
authors.lastname: Perek-Polnik
authors.forename: Ewa
authors.initials: E
authors.lastname: Kowalewska
authors.forename: Aneta
authors.initials: A
authors.lastname: Czajńska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Syczewska
authors.forename: Kamila
authors.initials: K
authors.lastname: Czornak
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: Marcin
authors.initials: M
authors.lastname: Roszkowski
authors.forename: Krystyna H
authors.initials: KH
authors.lastname: Chrzanowska
mesh_terms: D000293:Adolescent; D018797:Cell Cycle Proteins / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000453:epidemiology / Q000235:genetics*; D008969:Molecular Sequence Data; D049932:Nijmegen Breakage Syndrome / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D011110:Polymorphism, Genetic; D018570:Risk Assessment
chemical_list: D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; C112156:NBN protein, human; D009687:Nuclear Proteins