ABSTRACT
DNA repair gene polymorphisms and mutations may influence cancer risk. The product of the NBS1 gene, nibrin, is functionally involved in the double-strand DNA break repair system. Heterozygous, germline mutations of the NBS1 gene are associated with an increased risk of tumours. Thus, common polymorphism and haplotypes of NBS1 may contribute to the risk of cancer. This study verified whether polymorphisms of the NBS1 gene may influence susceptibility to the development of childhood acute leukaemia. We genotyped six polymorphisms of the NBS1 gene in 157 children with acute leukaemia and 275 controls. The TT genotype of c.2071-30A>T polymorphism was higher in leukaemia patients than in controls. Genotyping data from the six polymorphic loci in NBS1 in leukaemia patients and controls were used to impute haplotypes. Two of the evaluated haplotypes were associated with significantly increased leukaemia risk (P=0.0038 and P<0.0001). Our results suggest that some specific haplotypes of the NBS1 gene may be associated with childhood leukaemia.
Subject(s)
Cell Cycle Proteins/genetics , Leukemia/genetics , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Polymorphism, Genetic , Acute Disease , Adolescent , Child , Child, Preschool , Gene Frequency , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , InfantABSTRACT
Homozygous mutation 657del5 within the NBS1 gene is responsible for the majority of Nijmegen breakage syndrome (NBS) cases. NBS patients are characterised by increased susceptibility to malignancies mainly of lymphoid origin. Recently it has been postulated that heterozygous carriers of 657del5 NBS1 mutation are at higher risk of cancer development. The aim of the study was to analyse the frequency of I171V mutation in NBS1 gene in 270 women with breast cancer, 176 patients with larynx cancer, 81 with second primary tumours of head and neck, 131 with colorectal carcinoma and 600 healthy individuals. I171V mutation was present in 17 cancer patients compared with only one in healthy individuals. This constitutes 2.58% in studied patients with malignancies and 0.17% in the control group (P=0.0002; relative risk 1.827; odds ratio 15.886; 95% confidence interval 2.107-119.8). Since DNA was isolated from non malignant cells, all mutations found in cancer patients appeared to be of germinal origin. It can be concluded that NBS1 allele I171V may be a general susceptibility gene in solid tumours.
Subject(s)
Cell Cycle Proteins/genetics , Genetic Predisposition to Disease/genetics , Heterozygote , Mutation/genetics , Neoplasms/genetics , Nuclear Proteins/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Risk FactorsABSTRACT
The high incidence of multiple primary tumors (MPT) is a significant problem in head and neck tumor treatment. Recent studies suggest that carriers of heterozygous mutations in the NBS1 gene have an increased risk of malignant tumor development. The aim of our research was to assess the frequency of NBS1 mutations in patients with larynx cancer only (LC) and with MPT. The MPT group consisted of patients with one cancer localized to the larynx (primary or second) and another at another site. DNA from 175 patients with LC and 93 patients with MPT was analyzed using the single-strand conformation polymorphism method and direct sequencing. We found nine carriers of the I171V mutation among these 268 cancer patients and only one carrier among 500 population controls (0.2%). Four carriers of the I171V mutation were detected among 175 LC patients (2.3%) and five among 93 patients with MPT (5.4%). The frequencies of the I171V mutation carriers in LC and MPT patients were significantly higher than in controls (odds ratio [OR] = 11.7, confidence interval [CI] 1.3-105.2, P = 0.0175 and OR = 28.35, CI 3.27-245.7, P = 0.0005, respectively). In one individual with LC, a novel molecular variant, c.1222 A > G (p.K408E), was identified. No carriers of R215W or 657del5 NBS1 mutations were found in the present study. These findings imply that heterozygous carriers of the I171V mutation are prone to the development of larynx cancer and may, in addition, display an increased risk of second tumors at other sites.
Subject(s)
Amino Acid Substitution , Cell Cycle Proteins/genetics , Laryngeal Neoplasms/genetics , Mutation , Nuclear Proteins/genetics , Adult , Aged , Aged, 80 and over , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , DNA, Neoplasm/isolation & purification , Genetic Carrier Screening , Humans , Laryngeal Neoplasms/epidemiology , Lymphocytes/chemistry , Middle Aged , Neoplasms, Multiple Primary/genetics , Risk FactorsABSTRACT
The homozygous 657del5 mutation, called Slavic mutation, of the NBS1 gene, causes the Nijmegen Breakage Syndrome (NBS). This syndrome is connected with a high incidence of malignancies in early childhood. A high frequency of NBS heterozygotes was found among patients with melanoma, breast, ovary and prostate cancer. The aim of our research was to determine the frequency of 657del5 mutation of the NBS1 gene in the population of Wielkopolska province. For this purpose, we analysed blood samples from anonymous Guthrie cards. In a group of 2090 newborns from the whole province, we found 16 heterozygous mutation carriers. The frequency of 1/131 is higher than 1/190 reported for populations from other regions in Poland. We observed differential regional distribution of heterozygous 657del5 mutation carriers within the province: among 464 samples from the eastern part of Wielkopolska we found 6 carriers (1/77), in contrast to the southern part without any carrier among 625 samples analysed. The high mean frequency of heterozygous 657del5 mutation (1/131) in Wielkopolska province may be associated with cancer incidence in this region.
