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.

Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development

“…However, such an association was not observed for solid malignancies in children (11). By contrast, Ciara et al (19) reported an association between this variant and childhood medulloblastoma. Nonetheless, the in vitro studies conducted on cells derived from heterozygous carriers of the p.I171V variant have demonstrated that, per se, this variant does not play a crucial role in tumorigenesis (20).…”

Pediatric Medulloblastoma: The Role of Heterozygous Germ-Line Mutations in the NBN Gene

“…In children, the vast of majority of cancers observed in NBN carriers are lymphoid malignancy (Chrzanowska et al 2006 ;Mosor et al 2006 ) . There is also evidence that NBN mutations predispose to childhood medulloblastoma (Ciara et al 2010 ) .…”

“…Simultaneously, studies evaluating a role of mutational inactivation of DNA repair genes in human medulloblastoma development indicate that changes within genes coding proteins involved in the MRN complex and cooperative proteins seems to be particularly important. Germ-line mutations in medulloblastoma were found in the NBN gene, a part of the MRN complex, as well as in the BRCA2 gene, which is closely related to this complex (Ciara et al 2010 ;Of fi t et al 2003 ) . In addition, germ-line mutations were found in the PMS2 gene belonging to the mismatch repair genes group (MMR) that shares the responsibility for DNA repair with the MRN complex, as well as in the TP53 gene, a tumor suppressor indirectly activated by the MRE11-RAD50-NBN complex (Mirzoeva et al 2006 ) (Table 13.2 ).…”

“…While reduced levels of NBN can promote cancer development through de fi ciency in DSBs recognition and repair together with disturbance of cell cycle checkpoints, the activation of tumorigenesis via overexpression of NBN has still not been demonstrated (Dzikiewicz-Krawczyk 2008 ) . Furthermore Frappart et al ( 2005 ) reported that de fi ciency of Nbn in murine neuron cells leads to genomic instability and activation of the ATM/ p53-mediated DNA damage response, as well as Ciara et al ( 2010 ) proliferation defects of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Disruption of proliferation and/or uncontrolled apoptosis were the cause of the extensive cell loss and abnormal development observed in the cerebellum.…”

“…Ciara et al ( 2010 ) screened a total of 104 patients (age range 1.69-18 years) with medulloblastoma and identi fi ed seven heterozygous carriers of two different germ-line mutations, c.511A > G (p.I171V in exon 5) and c.657_661del5 (p.Lys219fsX19 in exon 6) localized in the highly conserved BRCT tandem domains. The c.511A > G mutation was present in 3.85% (1/26) of the medulloblastoma cases, which was three times higher (OR = 3.00; 95% CI: 2.94-3.06) than calculated for the control group, 1.28% (1/78); the difference was statistically signi fi cant ( p = 0.0241 ).…”