Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients.
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.
Ciara
Elżbieta
E
Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
Piekutowska-Abramczuk
Dorota
D
Popowska
Ewa
E
Grajkowska
Wiesława
W
Barszcz
Sławomir
S
Perek
Danuta
D
Dembowska-Bagińska
Bożenna
B
Perek-Polnik
Marta
M
Kowalewska
Ewa
E
Czajńska
Aneta
A
Syczewska
Małgorzata
M
Czornak
Kamila
K
Krajewska-Walasek
Małgorzata
M
Roszkowski
Marcin
M
Chrzanowska
Krystyna H
KH
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
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; C112156:NBN protein, human; D009687:Nuclear Proteins