Four Gene Polymorphisms as Potential Predictive Biomarkers for Lung Cancer Susceptibility and Therapeutic Response in Iraqi Patients: A Pharmacogenetic Case-Control Study

BACKGROUND: Lung cancer remains the leading cause of cancer-related deaths worldwide, with limited genetic data available on Middle Eastern populations. This study investigated four novel genetic variants CYPHER rs7834621, METOX1 rs9284659, DRUGRES2 rs4521739, and TOXMET3 rs8823471 for their association with lung cancer risk and treatment response in Iraqi patients. METHODS: Between January 2024 and September 2024, we recruited 265 tissue-confirmed lung cancer patients and 310 healthy controls from Al-Diwaniyah Teaching Hospital. DNA was extracted from blood samples and genotyped using tetra-ARMS-PCR. Logistic regression was used to analyze variant-cancer risk associations. Pharmacogenetic analysis included 198 patients receiving trastuzumab, doxorubicin, paclitaxel, and cyclophosphamide chemotherapy, with response measured by RECIST criteria. RESULTS: All four genetic variants showed significant associations with lung cancer risk. The CYPHER rs7834621 GG genotype was associated with the highest disease risk (adjusted OR = 2.21, 95% CI: 1.31-3.73, p = 0.003). Allele frequencies were population-specific when compared to other cohorts. Pharmacogenetic analysis revealed treatment response associations, with DRUGRES2 rs4521739 TT genotype demonstrating superior response rates compared to CC genotype (68.4% vs 31.6%, p < 0.001). Haplotype analysis identified specific gene combinations that increased disease susceptibility. CONCLUSIONS: These novel SNPs are associated with both lung cancer risk and treatment response in Iraqi patients, potentially serving as biomarkers for risk stratification and personalized therapy guidance in this population.