Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers
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Carlos Benítez-Buelga1, Juan Miguel Baquero1, Tereza Vaclova1, Victoria Fernández1, Paloma Martín1,4, Lucia Inglada-Perez2,4, Miguel Urioste3,4, Ana Osorio1,4 and Javier Benítez1,4
1Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
2Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
3Familial Cancer Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain
4Spanish Network on Rare Diseases (CIBERER), Madrid, Spain
Javier Benítez, email: jbenítez@cnio.es
Keywords: BRCA1 and BRCA2; NEIL2 polymorphism cancer risk modifier; mRNA levels; oxidative DNA damage
Received: March 28, 2017 Accepted: October 27, 2017 Published: November 23, 2017
In this report, we have tried to gain molecular insight into a single nucleotide polymorphism (SNP) in the NEIL2 gene previously identified as “cancer risk modifier” for BRCA2 mutation carriers.
To that end, we studied the role of this SNP (rs804271) on NEIL2 transcriptional regulation, oxidative DNA damage and genome instability in two independent set of samples: The first one was a series of eighty-six BRCA1 and BRCA2 mutation carriers and eighty non-carrier controls in which we evaluated the effect of the SNP on NEIL2 gene expression and oxidative DNA damage accumulation. The second was a set of twenty lymphoblastoid cell lines (LCLs), thirteen BRCA1 mutation carriers and seven non-carriers control, that were used to analyze the correlation between NEIL2 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 BRCA2 mutation carriers. We hypothesize that due to the SNP impact on NEIL2 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.
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