Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
Acta Neuropathol. 2010 Mar;119(3):325-34. doi: 10.1007/s00401-009-0608-y. Epub 2009 Nov 12.
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.
NBN（NBS1）基因属于双链断裂修复基因群。这些基因中的任何突变都会导致基因组不稳定综合征，并促进癌变。NBN 基因突变导致尼曼匹克破碎综合征（NBS）纯合子以及 NBN 杂合子的肿瘤风险增加。NBS 患者会发展出不同类型的恶性肿瘤；在实体肿瘤中，髓母细胞瘤（MB），即小脑的胚胎性肿瘤，是最常报道的。大多数髓母细胞瘤是散发性的，其中一些发生在家族性癌症综合征中。有几个信号通路已知参与遗传性和散发性 MB。我们研究的目的是鉴定 NBN 基因选定外显子中的突变，并确定不同类型髓母细胞瘤患儿中最常见的 NBN 基因突变的频率。我们共筛选了 104 例 MB 患者，发现 7 例（6.7%）为 NBN 基因突变的两种不同种系突变的杂合携带者；他们均为经典型 MB。我们的结果表明，种系 NBN 基因突变（c.511A>G 和 c.657_661del5）的杂合携带者可能表现出对 MB 发病的易感性增加。髓母细胞瘤的风险估计比波兰普通人群高 3.0 倍（c.511A>G）和 4.86 倍（c.657_661del5）（p<0.05）。这些结果表明，杂合 NBN 种系突变可能有助于髓母细胞瘤的发病机制。
