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...

Objectives: Cytokines are potential new serum markers, especially desirable for malignancies with poor prognosis like non-small cell lung cancer (NSCLC). Methods: Cytokines, tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-8, soluble TNF (sTNF) RI, sTNF RII, soluble IL-2 receptor-α, IL-1 receptor antagonist (IL-1ra), IL-10, vascular endothelial growth factor, basic fibroblast growth factor, and macrophage (M-CSF) and granulocyte colony-stimulating factor, as well as tumor markers – carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and CYFRA 21.1 – were assessed in the sera of 103 untreated NSCLC patients, and these cytokines and tumor markers were refered to clinical parameters of the disease and to the overall survival of patients evaluated during a 6-year follow-up. Results: Most of the factors analyzed were found to be elevated in the sera of NSCLC patients, and increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers; IL-6 and IL-1ra levels were significantly different in patients with squamous cell versus adenocarcinoma; IL-6 and IL-10 were related to the tumor size, while IL-6 and M-CSF levels significantly increased with disease progression. A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor. Conclusions: Increased pretreatment serum M-CSF level is a significant independent predictor of poor survival in patients with NSCLC.

These findings indicate that cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.

We investigated the correlations between serum levels of selected proinflammatory, hematopoietic and angiogenic cytokines and soluble cytokine receptors with the clinicopathological features and prognosis in soft tissue sarcoma patients. Serum levels of 9 cytokines (TNF␣, IL-1ra, IL-6, IL-8, IL-10, M-CSF, G-CSF, VEGF, bFGF) and 4 free cytokine receptors (sIL-2R␣, sIL-6R, TNFRI, TNFRII) were measured by means of an enzyme-linked immunoadsorbent assay kit in 156 soft tissue sarcoma patients before the treatment and in 50 healthy controls. Serum levels of 10 cytokines and cytokine receptors were also assayed during patients' follow-up after the treatment. Significantly elevated pretreatment serum levels of 11/13 cytokines and cytokine receptors were found in sarcoma patients, as compared to healthy controls.