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

  • Authors:
    • İzzet Özgürlük
    • Haktan Bağış Erdem
    • Mustafa Tarık Alay
    • Okan Oktar
    • Firdevs Şahin-Duran
    • Ezgi Çevik‑Demir
    • Aysu Yeşim Tezcan
    • Hüseyin Levent Keskin
  • View Affiliations / Copyright

    Affiliations: Department of Obstetrics and Gynecology, Ankara Etlik City Hospital, Ankara 06170, Türkiye, Department of Medical Genetics, Ankara Etlik City Hospital, Ankara 06170, Türkiye, Department of Gynecological Oncology, Ankara Etlik City Hospital, Ankara 06170, Türkiye, Department of Pathology, Ankara Etlik City Hospital, Ankara 06170, Türkiye
    Copyright: © Özgürlük et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 117
    |
    Published online on: January 23, 2026
       https://doi.org/10.3892/ol.2026.15470
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Abstract

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.

View Figures

Figure 1

Fold change in mtCN level according
to cervical disease category. ***P<0.001, ****P<0.0001. ns,
not significant; mtCN, mitochondrial DNA copy number; HSIL,
high-grade squamous intraepithelial lesion; LSIL, low-grade
squamous intraepithelial lesion.

Figure 2

Fold change in mtCN level according
to HPV risk status. *P<0.05. mtCN, mitochondrial DNA copy
number; HPV, human papillomavirus.

Figure 3

Fold change in mtCN level according
to smoking status. *P<0.05. mtCN, mitochondrial DNA copy
number.

Figure 4

Comparison of receiver operating
characteristics curves for all possible models. The triple model
comprising cervical disease category, smoking and HPV status is the
most successful for cervical cancer risk classification. HPV, human
papillomavirus.

Figure 5

Receiver operating characteristic
curve for the triple model, which combines cervical disease
category, smoking and human papillomavirus status. AUC, area under
the curve.
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Copy and paste a formatted citation
Spandidos Publications style
Özgürlük I, Erdem HB, Alay MT, Oktar O, Şahin-Duran F, Çevik‑Demir E, Tezcan AY and Keskin HL: <p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>. Oncol Lett 31: 117, 2026.
APA
Özgürlük, I., Erdem, H.B., Alay, M.T., Oktar, O., Şahin-Duran, F., Çevik‑Demir, E. ... Keskin, H.L. (2026). <p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>. Oncology Letters, 31, 117. https://doi.org/10.3892/ol.2026.15470
MLA
Özgürlük, I., Erdem, H. B., Alay, M. T., Oktar, O., Şahin-Duran, F., Çevik‑Demir, E., Tezcan, A. Y., Keskin, H. L."<p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>". Oncology Letters 31.3 (2026): 117.
Chicago
Özgürlük, I., Erdem, H. B., Alay, M. T., Oktar, O., Şahin-Duran, F., Çevik‑Demir, E., Tezcan, A. Y., Keskin, H. L."<p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>". Oncology Letters 31, no. 3 (2026): 117. https://doi.org/10.3892/ol.2026.15470
Copy and paste a formatted citation
x
Spandidos Publications style
Özgürlük I, Erdem HB, Alay MT, Oktar O, Şahin-Duran F, Çevik‑Demir E, Tezcan AY and Keskin HL: <p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>. Oncol Lett 31: 117, 2026.
APA
Özgürlük, I., Erdem, H.B., Alay, M.T., Oktar, O., Şahin-Duran, F., Çevik‑Demir, E. ... Keskin, H.L. (2026). <p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>. Oncology Letters, 31, 117. https://doi.org/10.3892/ol.2026.15470
MLA
Özgürlük, I., Erdem, H. B., Alay, M. T., Oktar, O., Şahin-Duran, F., Çevik‑Demir, E., Tezcan, A. Y., Keskin, H. L."<p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>". Oncology Letters 31.3 (2026): 117.
Chicago
Özgürlük, I., Erdem, H. B., Alay, M. T., Oktar, O., Şahin-Duran, F., Çevik‑Demir, E., Tezcan, A. Y., Keskin, H. L."<p>Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer</p>". Oncology Letters 31, no. 3 (2026): 117. https://doi.org/10.3892/ol.2026.15470
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