Abstract
BackgroundOvarian cancer (OC) is the most lethal gynecological cancer, worldwide, largely due to its vague and nonspecific early stage symptoms, resulting in most tumors being found at advanced stages. Moreover, due to its relative rarity, there are currently no satisfactory methods for OC screening, which remains a controversial and cost-prohibitive issue. Here, we demonstrate that Papanicolaou test (Pap test) cervical scrapings, instead of blood, can reveal genetic/epigenetic information for OC detection, using specific and sensitive DNA methylation biomarkers.ResultsWe analyzed the methylomes of tissues (50 OC tissues versus 6 normal ovarian epithelia) and cervical scrapings (5 OC patients versus 10 normal controls), and integrated public methylomic datasets, including 79 OC tissues and 6 normal tubal epithelia. Differentially methylated genes were further classified by unsupervised hierarchical clustering, and each candidate biomarker gene was verified in both OC tissues and cervical scrapings by either quantitative methylation-specific polymerase chain reaction (qMSP) or bisulfite pyrosequencing. A risk-score by logistic regression was generated for clinical application.One hundred fifty-one genes were classified into four clusters, and nine candidate hypermethylated genes from these four clusters were selected. Among these, four genes fulfilled our selection criteria and were validated in training and testing set, respectively. The OC detection accuracy was demonstrated by area under the receiver operating characteristic curves (AUCs) in 0.80–0.83 of AMPD3, 0.79–0.85 of AOX1, 0.78–0.88 of NRN1, and 0.82–0.85 of TBX15. From this, we found OC-risk score, equation generated by logistic regression in training set and validated an OC-associated panel comprising AMPD3, NRN1, and TBX15, reaching a sensitivity of 81%, specificity of 84%, and OC detection accuracy of 0.91 (95% CI, 0.82–1) in testing set.ConclusionsOvarian cancer detection from cervical scrapings is feasible, using particularly promising epigenetic biomarkers such as AMPD3/NRN1/TBX15. Further validation is warranted.
Highlights
Ovarian cancer (OC) is the most lethal gynecological cancer, worldwide, largely due to its vague and nonspecific early stage symptoms, resulting in most tumors being found at advanced stages
The early-stage shift was demonstrated as 37.8%, 23%, and 24% in the annual multimodal screening (MMS) by serum Cancer antigen 125 (CA-125) interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound (TVU), and no screening groups, respectively, in UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial
The methylomics profiles from Taipei Medical University-A (TMU-A) ovarian tissue dataset, Australian Ovarian Cancer Study (AOCS)–ovarian tissue dataset and Taipei Medical University set B (TMU-B) cervical scraping dataset were used to identify highly differentially methylated (HDM) genes between serous OC and non-OC patients. These selected HDM genes belonged to the intersection of all statistically significantly hypermethylated genes shown in these three datasets
Summary
Ovarian cancer (OC) is the most lethal gynecological cancer, worldwide, largely due to its vague and nonspecific early stage symptoms, resulting in most tumors being found at advanced stages. One much-studied, potential early detection approach, the use of the serum biomarker cancer antigen 125 (CA125) and transvaginal ultrasound (TVU), was extensively examined in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, including 78,216 women, with a median follow-up up to 13 years. That study showed no mortality benefit across an OC screening and no screening arm This diagnostic evaluation yielded a high false-positive rate associated with surgical complications [3]. Another large OC screening trial, the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), observed more than 200,000 women, with a median follow-up of 11 years, revealing no significant reduction of mortality in the primary analysis. No clinical practice guideline has supported current OC screening tools, including TVU and CA-125, for the early detection of OC
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
