Abstract 4219: Mitochondrial DNA damage: A promising tool to screen cervical cancer risk

Abstract

Abstract Background: Cervical cancer is the 4th most common female cancer, accounting for 500,000 new cases and 200,000 deaths across the world. 99% of cervical cancer is due to infection by human papillomavirus (HPV). The factors leading to HPV integration and induced carcinogenesis are not entirely clear, but high DNA damage levels have been proposed to play a role in HPV integration. Chronic HPV infection increases DNA damage and reduces DNA repair, leading to even higher DNA damage levels. Recently, we showed that the levels of nuclear DNA (nDNA) damage are a potential biomarker predictive of cancer risk. Mitochondrial DNA (mtDNA) damage has been reported to be more persistent than nDNA damage. We have previously demonstrated a good correlation between mtDNA and nDNA damage. Herein, we performed a pilot study to assess whether the levels of mtDNA damage can be used as a potential tool to screen cancer risk. Aims: (1) To measure determine whether the amount of mtDNA damage differs between cervical samples with distinct pathologies. (2) To determine whether the number of mtDNA lesions correlates with the grade of cervical dysplasia. Methods: Ethics Committee approval and written informed consent was obtained from all participants. Samples from 25 patients were collected from the endocervix during a pelvic exam in the Dysplasia Clinic. Samples for DNA damage studies were collected by cytobrush and DNA extracted as previously reported. Demographic and risk factor data were collected through detailed questionnaires. Clinicopathologic data was abstracted from the medical chart. The amount of mtDNA damage was quantified by a long-run real-time PCR-based DNA-damage quantification (LORDQ) assay. Data were analyzed by Student's t-tests. Logistic regression analysis was done modeling the probability of having present pathology risk. Results: Histopathological reports indicated that 9 cervical samples were normal (C0) and 16 had cervical dysplasia. Dysplasia samples were as follows: 9 low-grade squamous intraepithelial lesions (LSILs or C1) and 7 high-grade squamous intraepithelial lesions (HSILs or C2/3). The amount of mtDNA lesions per 10,000 bases were increased two-fold in LSILs or C1 cases and three-fold in HSILs or C2/3 cases when compared to C0. Regression analysis showed no significant correlation between age, race, smoking and drinking status compare with pathology risk. Conclusion: Our data show that mtDNA damage is the lowest in patients without cervical dysplasia and increases progressively with higher grades of dysplasia and correspondent cancer risk. This pilot study shows the feasibility of the approach and stresses the potential of using mtDNA damage to predict cervical cancer risk. Measuring mtDNA damage detection by LORDQ is less time consuming and more cost-effective than the measurement of nDNA damage. Larger population studies are urgently needed to fully assess the potential of this approach for cervical cancer risk. Citation Format: Balaji Sadhasivam, Camille C. Gunderson, Elizabeth H. Hahn, Sarah E. Johnston, Yan D. Zhao, Vengatesh Ganapathy, Lurdes Queimado. Mitochondrial DNA damage: A promising tool to screen cervical cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4219.