Genetic variation in the DNA glycosylase gene is associated with oxidative DNA damage in mutation carriers.

In this report, we have tried to gain molecular insight into a single nucleotide polymorphism (SNP) in the gene previously identified as "cancer risk modifier" for mutation carriers. To that end, we studied the role of this SNP (rs804271) on transcriptional regulation, oxidative DNA damage and genome instability in two independent set of samples: The first one was a series of eighty-six and mutation carriers and eighty non-carrier controls in which we evaluated the effect of the SNP on gene expression and oxidative DNA damage accumulation. The second was a set of twenty lymphoblastoid cell lines (LCLs), thirteen mutation carriers and seven non-carriers control, that were used to analyze the correlation between mRNA and/or protein levels, the oxidative and the double stranded break (DSB) DNA damage levels. Our results suggest that an excessive production of NEIL2 enzyme, associated with the SNP, may have a deleterious effect modifying cancer risk susceptibility in mutation carriers. We hypothesize that due to the SNP impact on transcriptional upregulation, a cascade of events may converge in the accumulation of oxidative DNA damage and its posterior conversion into DSBs for this specific group of patients.