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Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers

2017; Impact Journals LLC; Volume: 8; Issue: 70 Linguagem: Inglês

10.18632/oncotarget.22638

1949-2553

Carlos Benítez‐Buelga, Juan Miguel Baquero, Tereza Vaclová, María Victoria Fernández, Paloma Martín, Lucía Inglada‐Pérez, Miguel Urioste, Ana Osório, Javier Benı́tez,

RNA modifications and cancer

// Carlos Benítez-Buelga 1 , Juan Miguel Baquero 1 , Tereza Vaclova 1 , Victoria Fernández 1 , Paloma Martín 1, 4 , Lucia Inglada-Perez 2, 4 , Miguel Urioste 3, 4 , Ana Osorio 1, 4 and Javier Benítez 1, 4 1 Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain 2 Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain 3 Familial Cancer Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain 4 Spanish Network on Rare Diseases (CIBERER), Madrid, Spain Correspondence to: 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 ABSTRACT 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.