Screening of homologous recombination gene polymorphisms in lung cancer patients reveals an association of the NBS1-185Gln variant and p53 gene mutations.
Carcinogens present in tobacco smoke lead to several types of DNA damage in bronchial cells. In lung cancer, karyotype, allelotype, and fluorescence in situ hybridization analyses have demonstrated the common presence of aneuploidy, although its severity varies considerably among tumors. Deficiencies in the DNA-double strand break (DSB) repair system may be critical in the generation and persistence of chromosomal gains or losses during lung tumorigenesis. Therefore, we examined whether specific DSB repair gene polymorphisms were associated with an increase in tobacco-induced DNA damage, including gene mutations (p53 and KRAS) and chromosomal alterations. Nonsynonymous polymorphisms with a frequency higher that 0.1 at the XRCC3, NBS1, and BRCA2 genes were selected for the study. A PCR-RFLP analysis was performed to identify the Met241Thr, Glu185Gln, and Asn372His polymorphisms in the XRCC3, NBS1, and BRCA2 genes, respectively, in 109 lung cancer patients. Interestingly, the prevalence of p53 mutations was significantly greater among individual homozygous for the NBS1-185Gln allele (8 of 8, 100%) than among individuals for the wild-type allele (24 of 52, 46%). This increase in p53 mutation frequency was largely attributable to an increased prevalence of G-->T or C-->A transversions among these patients (P < 0.001). In addition, the association between this type of mutation and the NBS1-185Gln allele remained statistically significant after adjusting for age, smoking, and histological cell-type (odds ratio = 3.42 for heterozygous and odds ratio = 38.3 for NBS1-185Gln homozygous). Germ-line variants in the NBS1 gene may play a role in the lung carcinogenesis in cigarette smokers.
Medina
Pedro P
PP
Molecular Pathology Program, Spanish National Cancer Center (CNIO), 28029 Madrid, Spain.
Ahrendt
Steven A
SA
Pollan
Marina
M
Fernandez
Paloma
P
Sidransky
David
D
Sanchez-Cespedes
Montserrat
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D024522:Genes, BRCA2 / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D012907:Smoking / Q000009:adverse effects
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; C110901:X-ray repair cross complementing protein 3