Functional Variants of the NEIL1 and NEIL2 Genes and Risk and Progression of Squamous Cell Carcinoma of the Oral Cavity and Oropharynx

Abstract

Purpose: Human DNA glycosylases NEIL1and NEIL2 participate in oxidized base excision repair and protect cells from DNA damage. NEIL1 (MIM:608844) and NEIL2 (MIM:608933) variants may affect their protein functions, leading to altered cell death and carcinogenesis. To date, only one reported study has investigated the association between NEIL1 and NEIL2 polymorphisms and cancer risk. Experimental Design: Genotype and haplotypes of the NEIL1 NT_ 010194.16:g.46434077G>T (rs7182283) and g.46438282C>G (rs4462560) and NEIL2 NT_077531.3:g.4102971C>G (rs804270) polymorphisms were determined for 872 patients with newly diagnosed squamous cell carcinomas of the oral cavity and oropharynx (SCCOOP) and1,044 cancer-free non^Hispanic white control subjects frequency-matched by age and sex. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression, and false-positive report probabilities were also calculated. Results: We found no overall differences in the frequencies of alleles, genotypes, and haplotypes of NEIL1 g.46434077G>T and NEIL1 g.46438282C>G polymorphisms between cases and controls. However, the NEIL2 g.4102971CC genotype was associated with a significantly increased risk of SCCOOP (adjusted OR, 1.30; 95% CI, 1.02-1.65); this increase in risk was the highest among current alcohol drinkers (adjusted OR, 1.87; 95% CI, 1.28-2.72), particularly in patients with oropharyngeal cancer (adjusted OR, 1.35; 95 % CI, 1.04-1.76). The NEIL2 g.4102971CC genotype was also significantly associated with SCCOOP of advanced stages. Conclusions: Polymorphisms of the NEIL2 gene may be markers for risk and progression of SCCOOP, particularly in patients with oropharyngeal cancer. Larger studies are needed to confirm our findings.

DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

“…Several studies have been published showing associations between SNPs in NEIL2 and lung or oropharyngeal cancer risk [26], [27] but to our knowledge, no association with breast cancer risk has been reported. We hypothesize that the potential association observed in the present study could be explained by the interaction between NEIL2 and BRCA2 , each of them causing a deficiency in the BER and HR DNA repair pathways, respectively.…”

Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation

“…These combinatorial effects of genomic damage and innate inflammation due to NEIL2 deficiency could play a critical role in the development of breast cancer in BRCA2 carriers but also in other diseases as well. Notably, we and others have reported the association of some NEIL2 SNPs with lung and oropharyngeal cancer risk (19,80). Therefore, understanding the molecular mechanisms of such combinatorial responses using Neil2-null mice as an experimental tool may help to explain the previously proposed link of oxidative stress and inflammation to various pathologies, and the knowledge gained from such studies should ultimately benefit human health.…”

Induction of NEIL1 and NEIL2 DNA glycosylases in aniline-induced splenic toxicity

“…Also, NEIL1 and NEIL2 variants may affect their functions, leading to altered cell death and carcinogenesis. Study suggests that polymorphisms of the NEIL2 gene may be markers for risk progression of squamous cell carcinomas of the oral cavity and oropharynx (Zhai et al, 2008). Furthermore, mitochondrial DNA from NEIL1−/− mice show increased level of steady-state DNA damage and deletions relative to wild-type controls (Vartanian et al, 2006).…”