Carrier frequency of mutation 657del5 in the NBS1 gene in a population of polish pediatric patients with sporadic lymphoid malignancies

Abstract

Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency 5 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence. ' 2005 Wiley-Liss, Inc.Key words: lymphoid tissue malignancies; childhood and adolescence; NBS1 gene; 657del5 mutation; Nijmegen breakage syndrome Nijmegen breakage syndrome (NBS) (OMIM *251260) is a human autosomal recessive disease characterized by microcephaly, immunodeficiency, hypersensitivity to ionizing radiation and a very high incidence of cancer, particularly of lymphoid origin.1,2 The disease seems to be more prevalent among Central and Eastern European populations, with Polish patients constituting approximately half of all registered NBS patients worldwide. The great majority of NBS patients (>90%) share a pathogenic truncating mutation, 657del5, within exon 6 of the NBS1 gene. 3The NBS1 gene encodes a protein called nibrin or p95NBS1, which forms a multimeric complex with hMRE11 and hRAD50 (N/M/R complex) involved in recombination repair of DNA double-strand breaks (DNA DSBs) in yeast and mammals.3,4 DNA DSBs occur as intermediates in physiological events, such as V(D)J recombination during early B and T cell development and immunoglobulin (Ig) class switch in mature B cells, but most frequently are generated by mutagenic agents such as ionizing radiation and radio-mimetic chemicals. DNA DSBs represent the most serious DNA damage, which, if not repaired accurately, can result in genomic instability, including chromosome rearrangements or gene mutations, and finally...

Association of the heterozygous germline I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia

“…8 It could be postulated that the R215W mutation in the Polish population does not contribute to the development of ALL. In accordance with our results is the observation of Chrzanowska et al, 5 who Table 1 Germline mutations of the NBS1 gene identified among common ALL patients Letter to the Editor found no carriers of the R215W mutation among 545 Polish pediatric patients with lymphoid malignancies. A further mutation in exon 6, identified in a single individual only, was the amino-acid substitution V210F.…”

“…The association of the 657del5 mutation with increased risk of hematological cancer has been recently shown. 3,5 In our study, we observed only one 657del5 mutation in c-ALL patients (1/134) and one in controls (1/195). Similar results were reported by several authors who failed to detect a significant contribution of the 657del5 mutation to lymphoproliferative disease development among both Slavic populations 5 and non-Slavic populations, such as in Germany 5 or Britain.…”

“…[4][5][6] In contrast, Varon et al 7 detected several point mutations in the NBS1 gene among 47 patients with childhood acute lymphoblastic leukemia (ALL). These point mutations all lead to amino acid substitutions, S93L, D95N, I171V and R215W.…”

Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene

“…(28,29) The aim of our research was to assess whether mutations in the NBS1 gene may contribute to the development of larynx cancer (LC) and MPT of the head and neck.…”

“…(21) Recent studies strongly suggest that heterozygous 657del5 mutation carriers have an elevated risk of malignant tumor development, especially of melanoma, (22,23) colon and rectum cancer, (23) prostate cancer, (24) ovarian cancer, (25) breast cancer (26,27) and NHL. (28,29) The aim of our research was to assess whether mutations in the NBS1 gene may contribute to the development of larynx cancer (LC) and MPT of the head and neck.…”