A study on the association between TP53 Arg72Pro, XRCC1 Arg399Gln, GSTP1 Ile105Val, and GSTM3 indel and the risk of cutaneous squamous cell carcinoma: a systematic review and meta-analysis

As one of the most frequent malignancies, cutaneous squamous cell carcinoma (cSCC) exhibits a rising occurrence, imposing a substantial burden on healthcare systems. This meta-analysis unveils the link to cSCC susceptibility of polymorphisms in Tumor Protein p53 (TP53 Arg72Pro, rs1042522), X-ray Repair Cross-Complementation Group 1 (XRCC1 Arg399Gln, rs25487), Glutathione S-Transferase Pi 1 (GSTP1 Ile105Val, rs1695), and the 3-bp insertion/deletion polymorphism in intron 6 of the Glutathione S-Transferase Mu 3 (GSTM3) gene. PubMed, Embase, Cochrane Library, as well as Web of Science were retrieved systematically to obtain pertinent case-control research until September 2024. The relations of TP53 Arg72Pro, XRCC1 Arg399Gln, GSTP1 Ile105Val, to the GSTM3 intron 6 insertion/deletion polymorphism (hereafter, GSTM3 indel) and cSCC risk were elucidated utilizing odds ratios (ORs) with 95% confidence intervals (CIs) in additive, dominant, recessive, homozygous, heterozygous, as well as allelic models. Heterogeneity was assessed using the Cochrane Q test and the I² statistic. To further explore potential sources of heterogeneity, subgroup analyses were conducted based on geographic region, sample size, source of controls, genotyping methods, and conformity with Hardy-Weinberg equilibrium. The robustness of the results was evaluated through sensitivity analyses. Publication bias was assessed using funnel plots and Egger’s test when ten or more eligible studies were included. This meta-analysis revealed no significant association between the TP53 Arg72Pro, XRCC1 Arg399Gln, GSTP1 Ile105Val, and the GSTM3 indel and the risk of cSCC across all genetic models and the risk of cSCC across all genetic models. However, these gene polymorphisms exhibited substantial population heterogeneity and model-dependent associations with cSCC risk. Among the five genetic models, excluding the recessive model, TP53 Arg72Pro polymorphism was associated with an increased cSCC risk in Asian populations. XRCC1 Arg399Gln polymorphism was associated with elevated cSCC risk in European populations under the additive, allelic, and homozygous models, whereas it was associated with a decreased risk in North American populations. Notably, GSTP1 Ile105Val displayed a bidirectional effect in European populations: it was associated with reduced risk under the additive, allelic, and recessive models, but with increased risk under the homozygous model. The GSTM3 indel showed no significant association in any analysis. Our findings suggest that TP53 Arg72Pro, XRCC1 Arg399Gln, GSTP1 Ile105Val, and the GSTM3 indel are unlikely to be risk factors for cSCC. Further well-designed case-control studies are warranted to comprehensively assess the potential roles of these four polymorphisms in cSCC susceptibility.