Abstract
BackgroundAlthough human papillomavirus (HPV) infection has been regarded as the cause of cervical cancer in over 99% of cases, only a small fraction of HPV-infected women develop this malignancy. Emerging evidence suggests that alterations of mitochondrial DNA copy number (mtCN) may contribute to carcinogenesis. However, the relationship between mtCN and cervical cancer remains undetermined.MethodsThe current study included 591 cervical cancer cases and 373 cancer-free controls, all of whom were infected with high-risk HPV. Relative mtCN in cervical cancer exfoliated cells was measured by qRT-PCR assays, and logistic regression analysis was performed to compute odds ratios (ORs) and 95% confidence intervals (CIs). Interaction between mtCN and HPV types was assessed by using the Wald test in logistic regression models.ResultsHPV16, 18, 52, and 58 were the most common types in both case and control groups. Median mtCN in cases was significantly higher than that in controls (1.63 vs. 1.23, P = 0.03). After adjustment for age and HPV types, the highest quartile of mtCN was associated with increased odds of having cervical cancer (OR = 1.77, 95% CI = 1.19, 2.62; P < 0.01), as compared to the lowest quartile. A dose-response effect of mtCN on cervical cancer was also observed (Ptrend < 0.001). The interaction between mtCN and HPV types was statistically nonsignificant.ConclusionsIn women who test HPV positive, the increase of mtCN in cervical exfoliated cells is associated with cervical cancer. This suggests a potential role of mtCN in cervical carcinogenesis.
Highlights
Human papillomavirus (HPV) infection has been regarded as the cause of cervical cancer in over 99% of cases, only a small fraction of human papillomavirus (HPV)-infected women develop this malignancy
Of the 5066 women who asked for outpatient gynecological consultation in Cancer Institute and Hospital during the same period and were free of liquid-based cytological abnormalities but were high-risk HPV positive were included as cancer-free individuals
Cervical cancer patients had a higher proportion of HPV16 infection (54.65% vs. 19.57%, P < 0.001) but lower proportions of HPV52 (17.43% vs. 27.08%, P < 0.001) and HPV58 (9.31% vs. 15.55%, P = 0.005), as compared to the control group
Summary
Human papillomavirus (HPV) infection has been regarded as the cause of cervical cancer in over 99% of cases, only a small fraction of HPV-infected women develop this malignancy. Emerging evidence suggests that alterations of mitochondrial DNA copy number (mtCN) may contribute to carcinogenesis. An investigation of new triage approaches for HPV-positive women is important to improve the identification of individuals at high risk of cervical cancer. Mitochondrial DNA (mtDNA) is an extra-chromosomal circular, double-stranded DNA in eukaryotic cells [8]. It consists of 16.5 kilobase pairs that encode 37 genes involved in various cellular activities, including energy metabolism, free oxygen radical generation, and cell apoptosis [9]. Altered mtDNA copy number (mtCN) could affect the expression and function of mitochondrial genes, leading to abnormal cellular metabolism and proliferation [11]. When cancer progresses to advanced stages, cumulative damages to mitochondria may elicit mtDNA degradation and decompensation, resulting in a decrease in mtCN and the Warburg effect [21, 22]
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