DNA repair gene polymorphisms and risk of head and neck cancer in the Tunisian population Rim Khlifi 1,2 , Imen Kallel 2 , Bouthaina Hammami 3 , Amel Hamza-Chaffai 1 , Ahmed Rebai 2 1 Marine Ecotoxicology, UR 09-03, Sfax University, IPEIS, Sfax, Tunisia; 2 Bioinformatics Unit, Centre of Biotechnology of Sfax, Sfax, Tunisia; 3 Department of Otorhinolaryngology, Habib Borguiba Hospital, Sfax, Tunisia Altered activity of DNA repair enzymes may be involved in modulating cancer susceptibility and pathogenesis of head and neck cancer (HNC). We conducted a case– control study to test the association between three common single-nucleotide polymorphisms of XRCC1, ERCC2, and ERCC3 genes with HNC risk in Tunisian patients. To the best of our knowle dge, this is the first report on polymorphisms in XRCC1, ERCC2, and ERCC3 and susceptibility to HNC in our population. The geno- type analyses of XRCC1 Arg399Gln, ERCC2 Lys751Gln, and ERCC3 7122 A>G polymorphisms for 169 HNC patients, and 261 controls were performed using the PCR-based restriction fragment length polymorphism. Stratification of the populations according to smoking and drinking habits and occupational exposure high- lighted the importance of tobacco, alcohol, and toxic substance as three risk co-factors for the development of HNC. Our study suggests that only the XRCC1 Arg399Gln polymorphism was associated with the risk of HNC in the Tunisian population (OR = 2.04; P = 0.001). Further- more, the risk of HNC was associated with XRCC1 Arg399Gln polymorphism stratified by occupational exposure status (OR = 2.29; P = 0.024). However, no statistically significant association was observed between the risk of developing HNC and the ERCC2 Lys751Gln and ERCC3 A>G polymorphisms. These data suggest that the XRCC1 Arg399Gln polymorphism is associated with an increased risk of developing HNC, because it corre- lates with occupational exposure in Tunisian population. J Oral Pathol Med (2013) Keywords: ERCC2 and ERCC3 genes; head and neck cancer; occupational exposure; polymorphisms; XRCC1 Introduction Head and neck cancer (HNC) is the fifth most common cancer worldwide, it is associated with low survival and high morbidity when diagnosed in an advanced stage (1), accounting for almost 500 000 newly diagnosed cancer cases per year (2). HNC provides an excellent tumor model for investigating gene–environmental interactions because of the strong association with several risk factors, such as tobacco and alcohol consumption and occupational expo- sures (3). DNA repair is essential for the maintenance and protection of the cell genome from environmental hazards. Altered DNA repair capacity can lead to a higher risk of developing different types of cancer such as HNC (4–9). The human XRCC1 gene (X-ray repair cross-comple- menting gene 1) is located on chromosome 19q13.2–13.3 and encodes a protein that plays a key role in the single- strand break repair (SSBR) and base excision repair (BER) pathway (10). The data identify a novel pathway for mammalian SSBR and show a concerted role for XRCC1 in the initial step of processing damaged DNA ends (11). The G>A (rs25487) polymorphism causing arginine to gluta- mine substitution at codon 399 of exon 10 (Arg399Gln) occurs at a conserved residue in the poly (ADP-ribose) polymerase-binding domain of XRCC1 (12). The gene ERCC2 (excision repair cross-complementing group 2) or XPD (Xeroderma pigmentosum group D) is found at chromosomal location 19q13 and encodes the ERCC2/XPD protein (4). The ERCC2 protein is involved in the DNA nucleotide excision repair (NER) pathway. The ERCC2 Lys751Gln (rs13181) polymorphism is about 50 bases upstream from the poly (A) signal and may therefore alter XPD protein function. In ERCC2, a C-to-A change in codon 751 of exon 23 causes a lysine-to-glutamine substi- tution (12). The ERCC3 gene (excision repair cross-complementing group 3) or Xeroderma pigmentosum group B (XPB) is found in the chromosomal location 2q21 and encodes the ERCC3/ XPB protein (13). The ERCC3 protein is an essential ATP-dependent DNA helicase that functions as an integral component of the transcription factor IIH protein complex (14) which is required for transcription initiation as well as for NER and transcription-coupled repair (TCR). ERCC3 polymorphisms in the coding regions with a relatively high minor allele frequency (MAF) have been recently identified (15), such as ERCC3 7122 A>G (rs4150407). However, too few studies have investigated Correspondence: Rim Khlifi, Marine Ecotoxicology, UR 09-03, Sfax University, IPEIS, BP 805, 3018 Sfax, Tunisia. Tel: +21622646856, Fax: +21674275615, E-mail: rimkhlifi@yahoo.fr Accepted for publication July 23, 2013 doi: 10.1111/jop.12114 J Oral Pathol Med © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jop