Head and neck cancer (HNC) ranks as the seventh most prevalent cancer worldwide, with over 660,000 new diagnoses and 325,000 fatalities each year (Johnson et al., 2020, Sung et al., 2021). Around 90% of HNCs are classified as squamous cell carcinoma, originating from the epithelial lining of the oral cavity, pharynx, and larynx (Sung et al., 2021). In the United States (U.S.), HNC is responsible for roughly 67,000 cases each year and leads to 15,400 deaths (Siegel et al., 2023). In Europe, about 250,000 cases were reported in 2012, accounting for an estimated 4% of all cancer incidences, and resulted in 63,500 deaths (Gatta et al., 2015).

It has been observed that around 80% to 90% of squamous cell carcinomas of HNC in the U.S. have been linked to the consumption of tobacco and alcohol (Sturgis et al., 2004). Risk factors for HNC can include smoking, alcohol consumption, exposure to secondhand smoke and environmental carcinogens, infection with human papillomavirus (HPV), poor oral hygiene, unhealthy dietary habits, stress (Galbiatti et al., 2013, Guha et al., 2007, Mazul et al., 2017, Ragin et al., 2007), and genetic predispositions (Garajei et al., 2023, Garajei et al., 2022, Mohammadi et al., 2022, Mohammadi et al., 2021, Mozaffari et al., 2021).

Proteins involved in the nucleotide excision repair (NER) pathway are responsible for mending DNA damage (Melis et al., 2013, Simon et al., 2005). The excision repair cross-complementing (ERCC) gene family plays a role in mitigating DNA damage through nucleotide excision and repair (Gossage and Madhusudan, 2007, Simon et al., 2005). A deficiency in NER could result in heightened genomic instability, which could subsequently lead to tumors exhibiting more malignant phenotypic behavior (Mitchell et al., 2003, Niedernhofer et al., 2018, Simon et al., 2005). The ERCC1 gene is located on chromosome 19q13.2–q13.3 (Mari et al., 2017). ERCC1, a crucial component in NER, can serve as a predictive and prognostic indicator in cancer (Gossage & Madhusudan, 2007). The pathways regulating ERCC1 expression could be potential targets for cancer treatment (Gossage & Madhusudan, 2007).

The human xeroderma pigmentosum group C (XPC) protein is encoded by the XPC gene, which is localized on chromosome 3p25.1, spans 33 kb and consists of 16 exons and 15 introns (Zebian et al., 2019). In mice deficient in XPC, the accumulation of mutations is expedited and increased, leading to a higher incidence of tumors. XPC appears to play a role in initiating several responses induced by DNA damage (Melis et al., 2011, Zebian et al., 2022, Zebian et al., 2019). XPC is believed to function in eliminating oxidative DNA damage, maintaining redox homeostasis, and controlling the cell cycle (Melis et al., 2011, Nemzow et al., 2015).

Studies reported the association of ERCC1 (Fernández-Mateos et al., 2019, Lu et al., 2014) and XPC (Shen et al., 2001, Sugimura et al., 2006) polymorphisms with the HNC risk with different results. Meta-analyses reported this association for XPC including four and seven studies (Zhang et al., 2008, Zhang et al., 2014) and ERCC1 polymorphisms including eleven studies (Ding et al., 2015). We aimed to evaluate the association between the ERCC1 (rs3212986, rs735482, and rs2228000) and XPC (rs2228000, rs2228001, and intronic Poly (AT) insertion/deletion (PAT)) polymorphisms and the risk of HNC in a meta-analysis (17 studies for ERCC1 and 14 for XPC). The novelty of our meta-analysis lies in its comprehensive evaluation of the association between specific genetic polymorphisms and the risk of HNC. Specifically, our study focuses on the ERCC1 and XPC gene variants. While previous research has reported associations, our meta-analysis expands upon this by including more studies and conducting additional analyses. The rs11615 polymorphism is known as Asn118Asn, C118T, and T19007C; the rs3212986 polymorphism as C8092A or 3′UTR; the rs2228000 polymorphism as C21151T and Ala499Val; the rs2228001 polymorphism as A33512C and Lys939Gln; and the PAT polymorphism as intron 9.