Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer

Mitochondrial dysfunction has been increasingly implicated in carcinogenesis, with alterations in mitochondrial DNA (mtDNA) copy number reported across various cancer types. However, the role of mtDNA copy number changes in the progression from cervical intraepithelial neoplasia to invasive cervical cancer remains insufficiently characterized. The present study aimed to elucidate the association between mitochondrial DNA copy number (mtCN) variations and the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, and to evaluate the potential of mtCN as a biomarker for cervical cancer risk stratification. A cohort of 100 participants from the Gynecology and Obstetrics Clinic of Ankara Etlik City Hospital (Ankara, Türkiye) was enrolled. Cervical samples from the participants were categorized into four groups as follows: Normal (n=32), low‑grade squamous intraepithelial lesion (CIN1; n=21), high‑grade squamous intraepithelial lesion (CIN2/3; n=23) and cervical cancer (n=8). The remaining 16 samples were excluded from the analysis due to inadequate DNA yield or quality. Quantitative PCR was employed to quantify mtCN relative to nuclear DNA. Differences in mtCN according to disease category, smoking status and human papillomavirus (HPV) status were analyzed, and logistic regression modeling was performed to identify independent predictors of high‑risk cervical disease (HSIL and invasive cancer). The study revealed a statistically significant stepwise increase in mtCN concomitant with increasing disease severity, reaching the highest level in cervical cancer. Notably, HPV‑positive samples exhibited elevated mtCN levels compared with HPV‑negative samples. In addition, smoking was associated with a significant increase in mtCN within cervical tissues. A triple model comprising mtCN fold change, smoking status and HPV status demonstrated superior predictive performance for distinguishing high‑risk cervical disease, with a sensitivity of 79% and specificity of 92%. The findings indicate that mtCN alterations are associated with the progression of CIN to cervical cancer, particularly in cases who are HPV positive and smoke. To substantiate these findings and evaluate their clinical utility, larger longitudinal studies with standardized assessment protocols are imperative. However, the present study underscores the potential of mtCN as a biomarker for cervical cancer risk assessment and highlights the necessity for continued exploration into its role in tumorigenesis and diagnostic applications.