Mutations in the Nijmegen breakage syndrome gene in medulloblastomas.

PURPOSE: Cerebellar medulloblastoma is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutations is a rare autosomal recessive disease with clinical features that include microcephaly, mental and growth retardation, immunodeficiency, increased radiosensitivity, and predisposition to cancer. There may be functional interactions between NBS1 and the TP53 pathways. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of sporadic medulloblastomas.

EXPERIMENTAL DESIGN: Forty-two cases of medulloblastomas were screened for mutations in the NBS1 gene (all 16 exons) and the TP53 gene (exons 5-8) by single-stranded conformational polymorphism followed by direct DNA sequencing.

RESULTS: Seven of 42 (17%) medulloblastomas carried a total of 15 NBS1 mutations. Of these, 10 were missense point mutations and 5 were intronic splicing mutations. None of these were reported previously as germ-line mutations in NBS patients. No NBS1 mutations were detected in peritumoral brain tissues available in two patients. Of 5 medulloblastomas with TP53 mutations, 4 (80%) contained NBS1 mutations, and there was a significant association between TP53 mutations and NBS1 mutations (P = 0.001).

CONCLUSIONS: We provide evidence of medulloblastomas characterized by NBS1 mutations typically associated with mutational inactivation of the TP53 gene.