It has been suggested based on familial data that Nijmegen breakage syndrome (NBS) heterozygotes have an increased risk of malignant tumors. We found 15 carriers of the 657del5 mutation and 8 carriers of the R215W molecular variant of the NBS1 gene among 1,289 consecutive patients from Central Poland with various cancers and only 10 and 4 such carriers, respectively, in 1,620 controls from this region. Most of the 657del5 mutation carriers were found among patients with melanoma (4/105), non-Hodgkin lymphoma (2/ 42) and breast cancer (4/224) and of the 234 patients with colorectal carcinoma 3 carried the 657del5 mutation and 3 others the R215W molecular variant. The frequencies of 657del5 mutation carriers among patients with melanoma and non-Hodgkin lymphoma and of R215W carriers in patients with colorectal cancer were significantly higher than in controls (p < 0.01, < 0.05 and < 0.05 respectively). The pooled frequencies of 657del5 and R215W mutations in all cancer patients were also significantly higher than in controls (p < 0.05). Two carriers of the 657del5 mutation had second primary tumors. Malignant tumors among parents and siblings of 657del5 mutation carriers (14/77) were twice more frequent than in population controls. Three carriers of this mutation (2 probands with melanoma) reported melanoma in relatives. These results suggest strongly that NBS1 heterozygosity may be associated with elevated risk of some cancers. Larger studies are needed to evaluate the impact of the high frequency of germline NBS1 mutations on the cancer burden in the Slav populations. © 2004 Wiley-Liss, Inc. Key words: NBS1 gene; heterozygous mutation carriers; 657del5 mutation; R215W molecular variant; cancer riskThe chromosomal instability disorder, Nijmegen breakage syndrome (NBS), is characterized by microcephaly, growth retardation, immunodeficiency, hypersensitivity to X-irradiation and increased predisposition to lymphoid malignancy. 1 The gene mutated in NBS was identified in 1998. [2][3][4] Nibrin, the product of the NBS1 gene, is part of the MRE11/RAD50 complex, which is involved in the repair of DNA double strand breaks (DSBs). Double strand breaks are not only induced by mutagens but are also intermediates of DNA processing in immune gene rearrangements, the maintenance of telomeres, and in meiotic recombination. Nibrin is involved in the processing of all these types of DSBs. 2 This explains the complex NBS phenotype, including the very high incidence of lymphomas and other malignant tumors, which are the major cause of deaths among NBS patients already during childhood and adolescence. 5 The majority of NBS patients are of Central and Eastern European origin and share the common founder mutation in the NBS1 gene, 657del5. 6 NBS shares many clinical and cellular features with ataxiatelangiectasia (AT), and it was shown that they are also pathogenetically related. 7-10 Interestingly, the cancer risk in NBS1 homozygotes is higher than that of AT patients. 5 Heterozygous relatives of AT probands have an approximately 2...

The NBS1 gene mutation, 657del5, frequent in the Slavic populations of Central Europe, is found in most patients with Nijmegen breakage syndrome (NBS), a recessive autosomal disorder with a very high incidence of non-Hodgkin lymphoma (NHL). We have previously described 2 heterozygous 657del5 mutation carriers among 42 adult NHL probands from Central Poland. Here we report 6 additional carriers of the 657del5 mutation and 2 carriers of the pathogenic NBS1 R215W mutation, among 186 other NHL patients also from Central Poland. The 657del5 carrier frequency in the pooled group of these 228 patients was significantly higher than in population controls (OR 5.85, 95% CI: 2.29-15.00, p 5 0.0001). Interestingly, 4 of these carriers were found among 37 patients with gastrointestinal lymphoma (OR 19.52, 95% CI: 5.82-65.42, p 5 0.0002). These findings imply that heterozygous NBS1 germline mutations may contribute significantly to the overall incidence of NHL, especially of the gastrointestinal tract, in Central Europe. ' 2006 Wiley-Liss, Inc.

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