Genetic and expressional variations of APEX1 are associated with increased risk of head and neck cancer

Abstract

The aetiology of head and neck cancer (HNC) has been shown to be associated with genetic and certain environmental factors that produce DNA damage. Base excision repair (BER) genes are responsible for repair of DNA damage caused by reactive oxygen species and other electrophiles and therefore are good candidate susceptibility genes for HNC. Apurinic/apyrimidinic endonuclease-1 (APEX1) proteins have important functions in the BER pathway. In this case-control study, all exons of the APEX1 gene and its exon/intron boundaries were amplified in 300 HNC cases and 300 matched healthy controls and then analysed by single-stranded conformational polymorphism. Amplified products showing altered mobility patterns were sequenced and analysed. To confirm our observations, we examined APEX1 expression at mRNA level on 50 head and neck squamous cell carcinoma (HNSCC) and 50 normal control samples by quantitative real-time polymerase chain reaction. At germ line level, three novel mutations (13T > G, Ser129Arg and Val131Gly) of APEX1 were observed. The homozygous and heterozygous genotypes of APEX1 13T > G, Ser129Arg and Val131Gly appear to be significantly involved in the development of HNC. In the case of expressional level, APEX1 mRNA expression was positively correlated with tumour size, clinical stage and positive lymph node metastasis. Statistical analysis showed a significantly higher APEX1 mRNA level in HNC tumour tissue than in control samples. Our study demonstrated that APEX1 mutations and deregulation of APEX1 are associated with increased risk of HNC in the Pakistani population.

Germline Variations of Apurinic/Apyrimidinic Endonuclease 1 (APEX1) Detected in Female Breast Cancer Patients

“…This includes seven mutations in 5'UTR region, one in 3'UTR region, two intronic and four missense mutations. Out of these observed mutations 11 were novel and three already reported mutations (rs41561214, rs17112002 and Ser129Arg by Mahjabeen et al, 2013). Most of the mutations in 5'UTR, 3'UTR and intronic region were significantly higher in breast cancer patients compared-healthy control individuals.…”

“…Epidemiologic studies have linked single nucleotide polymorphisms (SNPs) in BER pathway genes-increased human cancer risk including breast cancer which have been evaluated in different populations in past by focusing on three key genes: X-ray repair cross-complementing protein 1 (XRCC1), 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease 1(APEX1) (Hu et al, 2001;Zhang et al, 2006;Lo et al, 2009;Lu et al, 2009;Li et al, 2011;Karahalil et al, 2012;Mahjabeen et al, 2013;Kim et al, 2013;Popanda et al, 2013 ). APEX1 is multifunctional protein playing an important role in DNA repair process through AP-endonucleolytic 3' phosphodiesterase, 3'-5' exonuclease and 3' phosphatase activities.…”

“…C-terminal domain performs DNA repair functions and protects cells from the cytotoxicity caused by the continuously accumulating exogenous and endogenous AP site mutation (Zhang and Wang, 2010). Structural prediction of Ser129Arg variant in APEX1 by Mahjabeen et al (2013), has shown no major change in protein structure compared with wildtype protein but APEX1-compromised cells are more susceptible to oxidative stress mainly due to reduced redox and 3'phosphodiestrase activity impacting cell survival, pushing it towards apoptosis (Fishel et al, 2007). Presence of identified missense mutations in both Redox and Repair domains signify that how repair process of DNA might be affected due to inhibition of Redox and repair activity of APEX protein.…”

“…All mutations observed in this study were heterozygous. Among identified mutations one 5'UTR (g.20923416C>T, rs41561214), one 3'UTR (20925669A>T, rs17112002) and one missense mutation (Ser129Arg, Mahjabeen et al, 2013) *PhyloP was used as a conservation score rating the nucleotides from "not conserved" (-14.1) to "highly conserved" (6.4) [ (Pollard et al, 2010). Align GVGD score: most likely deleterious (C65) to least likely deleterious (C0) GV (Grantham variation) and GD (Grantham R et al, 1974)].…”

Association between the APEX1 Asp148Glu polymorphism and prostate cancer, especially among Asians: a new evidence-based analysis

“…There are several polymorphisms in the APEX1 gene, of which Asp148Glu (rs1130409) has been associated with many cancers [14–16, 23–25, 27]. In 2001, Hu et al [33] conducted a study on the association between variants of APE1 and ionizing radiation, which suggested that the G allele transformed from T (Asp > Glu) is associated with mitotic delay in lymphocytes, providing greater sensitivity to ionizing radiation.…”