CDKN2A rs3088440 and CDKN2C rs12855 polymorphisms in cervical cancer: association with patients' survival

Background and objectives Cervical cancer remains one of the major public health challenges, holding the position as the fourth-most prevalent cancer affecting women worldwide. Persistent infection with human papillomavirus (HPV) is a necessary prerequisite for cervical carcinogenesis; however, it is increasingly recognized that additional cofactors contribute to disease initiation and progression, including genetic susceptibility, premature sexuality, high parity, and tobacco use. Growing attention is being directed toward the role of genetic variation in modulating individual susceptibility and influencing disease progression. In this context, CDKN2A and CDKN2C encode key regulators of cell cycle control that influence cell proliferation and may be implicated in carcinogenic pathways. Investigating single-nucleotide polymorphisms (SNPs) in these genes may enhance understanding of the molecular mechanisms underlying cervical cancer, enable the identification of higher-risk individuals, and support the development of more personalized preventive and therapeutic strategies. The present study aimed to evaluate the impact of CDKN2A rs3088440 and CDKN2C rs12855 on the clinicopathological characteristics of cervical cancer, as well as on patients' overall and progression-free survival outcomes. Material and Method In this study, CDKN2A rs3088440 and CDKN2C rs12855 were screened in 165 women with stage I-IV cervical cancer. Clinicopathological data, including age at diagnosis, tumor size, lymph nodes involvement, tumor histological grade, disease progression, distant metastasis status, and mortality status, were collected by oncologists. Genomic DNA was isolated from peripheral blood samples using a spin column-based extraction method. Genotyping of SNPs was performed using TaqMan probe assays on the QuantStudio™ 3 Real-Time PCR System. Associations between SNPs and clinicopathological characteristics of cervical cancer were evaluated using odds ratios (ORs) with 95% confidence intervals (CIs). Associations with survival outcomes were assessed using Kaplan-Meier (with the log-rank test) and Cox regression analyses, reporting hazard ratios (HR) and 95% CIs. Progression-free survival (PFS) was defined from diagnosis to local or distant disease progression, while overall survival (OS) was assessed from diagnosis to death or last follow-up. All statistical tests were conducted using IBM SPSS Statistics 30.0.0.0, and p<0.05 was considered statistically significant. The study was approved by the Kaunas Regional Biomedical Research Ethical Committee (numbers BE-2-10 and P1-BE-2-10/2014). Results In the cohort of 165 patients, the genotype distribution of CDKN2A rs3088440 was 85.5% GG, 13.3% GA, and 1.2% AA, with corresponding allele frequencies of 92.1% (G) and 7.9% (A). For CDKN2C rs12855, genotype frequencies were 92.7% CC and 7.3% CT, while allele frequencies were 96.4% (C) and 3.6% (T). No significant associations were observed between these genotypes or alleles and the clinicopathological characteristics of cervical cancer. However, survival analysis using Kaplan-Meier curves revealed a significant difference in OS according to CDKN2A rs3088440 (p=0.009) and CDKN2C rs12855 (p=0.020) genotypes. The CDKN2A rs3088440 AA genotype was associated with poorer OS, while the CDKN2C rs12855 CT genotype was linked to more favorable OS. These findings were further supported by Cox regression analysis, indicating an increased risk of death associated with CDKN2A rs3088440 AA genotype and a reduced risk associated with CDKN2C rs12855 CT (HR=6.564; 95% CI 1.566-27.519; p=0.010, and HR=0.134; 95% CI 0.018-0.979; p=0.048, respectively). Additionally, a significant association was observed between CDKN2A rs3088440 genotypes and PFS (p=0.034). It was estimated that the CDKN2A rs3088440 AA genotype was associated with worse PFS (HR=5.198; 95% CI 1.245-21.701; p=0.024). Conclusions and Recommendations The findings suggest that CDKN2A rs3088440 and CDKN2C rs12855 polymorphisms were associated with OS and PFS, highlighting their potential as prognostic biomarkers in cervical cancer; however, larger studies are required to confirm these associations and their clinical utility.