Hypermethylated PCDHGB7 as a universal cancer only marker and its application in early cervical cancer screening.
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ABSTRACT:
SUBMITTER: Dong S
PROVIDER: S-EPMC8214855 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
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Hypermethylated PCDHGB7 as a universal cancer only marker and its application in early cervical cancer screening.
Dong Shihua S Lu Qi Q Xu Peng P Chen Limei L Duan Xiaoling X Mao Zhanrui Z Zhang Baolong B Sui Long L Wang Yudong Y Yu Wenqiang W
Clinical and translational medicine 20210601 6
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Project description:Endometrial cancer (EC) is one of the most common gynecologic cancers in developed countries. Presently, it is imperative to develop a reliable, noninvasive, or minimally invasive detection method for EC. We explored the possibility of using DNA methylation marker from endometrial brush samples (with a "Tao brush") and cervical scrapes (with a "Pap brush") for early detection of EC. We analyzed the methylation data of EC and normal endometrial tissues from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data sets. An optimized methylation-sensitive restriction enzyme combined with real-time fluorescent quantitative PCR (MSRE-qPCR) was used for methylation detection. Included in the training set were 143 endometrial tissues, 103 Tao, and 109 Pap brush samples. The validation set included 110 Tao and 112 Pap brush samples. PCDHGB7 was significantly hypermethylated in EC compared with normal endometrial tissues in the TCGA and GEO data sets (AUC >0.95), which was verified in clinical samples. In the Pap brush samples, the AUC was 0.86 with 80.65% sensitivity and 82.81% specificity, whereas the Tao brush samples exhibited higher specificity (95.31%). The combination of Tao and Pap brush samples significantly increased the sensitivity to 90.32%. In the validation set, the final model yielded a sensitivity of 98.61%, specificity of 60.53%, positive predictive value of 82.56%, and negative predictive value of 95.83%. These results demonstrate the potential application of the novel methylation marker, hypermethylated PCDHGB7, in cervical scrapings and endometrial brush, which provides a viable, noninvasive, or minimally invasive method for early endometrial cancer detection across different clinical features and histologies to supplement current hysteroscopy diagnosis.
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Project description:BackgroundUrothelial carcinoma (UC) is the second most common urological malignancy. Despite numerous molecular markers have been evaluated during the past decades, no urothelial markers for diagnosis and recurrence monitoring have shown consistent clinical utility.MethodsThe methylation level of tissue samples from public database and clinical collected were analyzed. Patients with UC and benign diseases of the urinary system (BUD) were enrolled to establish TAGMe (TAG of Methylation) assessment in a training cohort (n = 567) using restriction enzyme-based bisulfite-free qPCR. The performance of TAGMe assessment was further verified in the validation cohort (n = 198). Urine samples from 57 UC patients undergoing postoperative surveillance were collected monthly for six months after surgery to assess the TAGMe methylation.ResultsWe identified TAGMe as a potentially novel Universal-Cancer-Only Methylation (UCOM) marker was hypermethylated in multi-type cancers and investigated its application in UC. Restriction enzyme-based bisulfite-free qPCR was used for detection, and the results of which were consistent with gold standard pyrosequencing. Importantly, hypermethylated TAGMe showed excellent sensitivity of 88.9% (95% CI: 81.4-94.1%) and specificity of 90.0% (95% CI: 81.9-95.3%) in efficiently distinguishing UC from BUD patients in urine and also performed well in different clinical scenarios of UC. Moreover, the abnormality of TAGMe as an indicator of recurrence might precede clinical recurrence by three months to one year, which provided an invaluable time window for timely and effective intervention to prevent UC upstaging.ConclusionTAGMe assessment based on a novel single target in urine is effective and easy to perform in UC diagnosis and recurrence monitoring, which may reduce the burden of cystoscopy. Trial registration ChiCTR2100052507. Registered on 30 October 2021.
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Project description:BACKGROUND: Tumor-derived aberrantly methylated DNA might serve as diagnostic biomarkers for cancer, but so far, few such markers have been identified. The aim of the present study was to investigate the potential of the MAL (T-cell differentiation protein) gene as an early epigenetic diagnostic marker for colorectal tumors. METHODS: Using methylation-specific polymerase chain reaction (MSP) the promoter methylation status of MAL was analyzed in 218 samples, including normal mucosa (n = 44), colorectal adenomas (n = 63), carcinomas (n = 65), and various cancer cell lines (n = 46). Direct bisulphite sequencing was performed to confirm the MSP results. MAL gene expression was investigated with real time quantitative analyses before and after epigenetic drug treatment. Immunohistochemical analysis of MAL was done using normal colon mucosa samples (n = 5) and a tissue microarray with 292 colorectal tumors. RESULTS: Bisulphite sequencing revealed that the methylation was unequally distributed within the MAL promoter and by MSP analysis a region close to the transcription start point was shown to be hypermethylated in the majority of colorectal carcinomas (49/61, 80%) as well as in adenomas (45/63, 71%). In contrast, only a minority of the normal mucosa samples displayed hypermethylation (1/23, 4%). The hypermethylation of MAL was significantly associated with reduced or lost gene expression in in vitro models. Furthermore, removal of the methylation re-induced gene expression in colon cancer cell lines. Finally, MAL protein was expressed in epithelial cells of normal colon mucosa, but not in the malignant cells of the same type. CONCLUSION: Promoter hypermethylation of MAL was present in the vast majority of benign and malignant colorectal tumors, and only rarely in normal mucosa, which makes it suitable as a diagnostic marker for early colorectal tumorigenesis.
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Project description:BackgroundTransvaginal measurement of cervical length (CL) has been advocated as a screening tool to prevent preterm birth, but controversy remains regarding the overall utility of universal screening.ObjectiveWe aimed to evaluate the acceptability of a universal CL screening program. Additionally we evaluated risk factors associated with declining screening and subsequent delivery outcomes of women who accepted or declined screening.Study designThis was a retrospective cohort study of transvaginal CL screening at a single institution from July 1, 2011, through December 31, 2014. Institutional protocol recommended transvaginal CL measurement at the time of anatomic survey between 17-23 weeks in all women with singleton, viable pregnancies, without current or planned cerclage, with patients able to opt out. Patients with CL ≤20 mm were considered to have clinically significant cervical shortening and were offered treatment. We assessed acceptance rate, risk factors for declining CL screening, and the trend of acceptance of CL screening over time. We also calculated the prevalence of CL ≤25, ≤20, and ≤15 mm, and estimated the association between CL screening and spontaneous preterm birth.ResultsOf 12,740 women undergoing anatomic survey during the study period, 10,871 (85.3%; 95% confidence interval [CI], 84.7-85.9%) underwent CL screening. Of those, 215 (2.0%) had a CL ≤25 mm and 131 (1.2%) had a CL ≤20 mm. After the first 6 months of implementation, there was no change in rates of acceptance of CL screening over time (P for trend = .15). Women were more likely to decline CL screening if they were African American (adjusted odds ratio [aOR], 2.17; 95% CI, 1.93-2.44), obese (aOR, 1.18; 95% CI, 1.06-1.31), multiparous (aOR, 1.45; 95% CI, 1.29-1.64), age <35 years (aOR, 1.24; 95% CI, 1.08-1.43), or smokers (aOR, 1.42; 95% CI, 1.20-1.68). Rates of spontaneous preterm birth <28 weeks were higher in those who declined CL screening (aOR, 2.01; 95% CI, 1.33-3.02).ConclusionUniversal CL screening was implemented successfully with 85% of women screened. Overall incidence of short cervix was low and women with significant risk factors for preterm birth were more likely to decline screening. Patients who declined CL screening were more likely to be African American, obese, multiparous, age <35 years, and smokers. Rates of early, but not late, spontaneous preterm birth were significantly higher among women who did not undergo CL screening.
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Project description:IntroductionLymph node status is a major prognostic factor in early-stage cervical cancer. Predicting the risk of lymph node metastasis is essential for optimal therapeutic management. The aim of the study was to develop a web-based application to predict the risk of lymph node metastasis in patients with early-stage (IA1 with positive lymph vascular space invasion, IA2 and IB1) cervical cancer.Materials and methodsWe performed a secondary analysis of data from two prospective multicenter trials, Senticol 1 and 2 pooled together in the training dataset. The histological risk factors were included in a multivariate logistic regression model in order to determine the most suitable prediction model. An internal validation of the chosen prediction model was then carried out by a cross validation of the 'leave one out cross validation' type. The prediction model was implemented in an interactive online application of the 'Shinyapp' type. Finally, an external validation was performed with a retrospective cohort from L'Hôtel-Dieu de Québec in Canada.ResultsThree hundred twenty-one patients participating in Senticol 1 and 2 were included in our training analysis. Among these patients, 280 did not present lymph node invasion (87.2%), 13 presented isolated tumor cells (4%), 11 presented micrometastases (3.4%) and 17 macrometastases (5.3%). Tumor size, presence of lymph-vascular space invasion and stromal invasion were included in the prediction model. The Receiver Operating Characteristic (ROC) Curve from this model had an area under the curve (AUC) of 0.79 (95% CI [0.69- 0.90]). The AUC from the cross validation was 0.65. The external validation on the Canadian cohort confirmed a good discrimination of the model with an AUC of 0.83.DiscussionThis is the first study of a prediction score for lymph node involvement in early-stage cervical cancer that includes internal and external validation. The web application is a simple, practical, and modern method of using this prediction score to assist in clinical management.
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Project description:This paper investigates the effect of expansion to near-universal health insurance coverage in Massachusetts on breast and cervical cancer screening. We use data from 2002 to 2010 to compare changes in receipt of mammograms and Pap tests in Massachusetts relative to other New England states. We also consider the effect specifically among low-income women. We find positive effects of Massachusetts health reform on cancer screening, suggesting a 4 to 5% increase in mammograms and 6 to 7% increase in Pap tests annually. Increases in both breast and cervical cancer screening are larger 3 years after the implementation of reform than in the year immediately following, suggesting that there may be an adjustment or learning period. Low-income women experience greater increases in breast and cervical cancer screening than the overall population; among women with household income less than 250% of the federal poverty level, mammograms increase by approximately 8% and Pap tests by 9%. Overall, Massachusetts health reform appears to have increased breast and cervical cancer screening, particularly among low-income women. Our results suggest that reform was successful in promoting preventive care among targeted populations.
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Project description:IntroductionScreening is an effective method for preventing cervical cancer. The present study aimed to determine the predictability of cervical cancer screening using the information-motivation-behavioral skills (IMB) model, as this model can help understand the factors that influence health-related behaviors.MethodThe present cross-sectional study examined 310 women aged 20 to 60 in Isfahan, Iran, between 2020 and 2021. To this end, comprehensive health centers and gynecology clinics of hospitals were randomly selected by lot. Women who met the study's inclusion criteria were selected via convenience sampling. An IMB skills questionnaire developed by researchers comprised the data collection tool. The data were analyzed using SPSS 22 software, descriptive and regression tests, and AMOS 24.0 software.FindingsApproximately 18.1% of the participants had never undergone routine cervical cancer screening. The regression model results indicated that the model components accurately predicted regular cervical cancer screening (P < 0.00). Path analysis revealed that information (β = 0.05, P = 0.002), motivation (β = 0.187, P = 0.026), and behavioral skills (β = 0.95, P < 0.001) were directly associated with regular cervical cancer screening. Furthermore, behavioral skills had the greatest direct effect on regular cervical cancer screening.Discussion and conclusionThe results demonstrated that the IMB model accurately predicted cervical cancer screening. Therefore, it is possible to improve cervical cancer screening in women by designing and implementing interventions based on this model's components, particularly those that improve behavioral skills.
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Project description:Human papilloma virus (HPV) DNA test was applied in cervical cancer screening as an effective cancer prevention strategy. The viral load of HPV generated by different assays attracted increasing attention on its potential value in disease diagnosis and progression discovery. In this study, three HPV testing datasets were assessed and compared, including Hybrid Capture 2 (n = 31,954), Aptima HPV E6E7 (n = 3269) and HPV Cobas 4800 (n = 13,342). Logistic regression models for diagnosing early cervical lesions of the three datasets were established and compared. The best variable factor combination (VL + BV) and dataset (HC2) were used for the establishment of six machine learning models. Models were evaluated and compared, and the best-performed model was validated. Our results show that viral load value was significantly correlated with cervical lesion stages in all three data sets. Viral Load and Bacterial Vaginosis were the best variable factor combination for logistic regression model establishment, and models based on the HC2 dataset performed best compared with the other two datasets. Machine learning method Xgboost generated the highest AUC value of models, which were 0.915, 0.9529, 0.9557, 0.9614 for diagnosing ASCUS higher, ASC-H higher, LSIL higher, and HSIL higher staged cervical lesions, indicating the acceptable accuracy of the selected diagnostic model. Our study demonstrates that HPV viral load and BV status were significantly associated with the early stages of cervical lesions. The best-performed models can serve as a useful tool to help diagnose cervical lesions early.
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Project description:OBJECTIVE:Evaluate the significance of BMRT HPV assay viral load and its performance for secondary screening. METHODS:BMRT-HPV reports type-specific viral loads/10,000 cells. We tested 1,495 physician collected, stored specimens from Chinese Multiple-center Screening Trial (CHIMUST), that were positive by Cobas, SeqHPV, and/or Cytology (≥LSIL); and 2,990 age matched, negatives in a nested case control study. We explored the relationship between BMRT HR-HPV viral load and cervical lesions, determined alternative CIN2+ cut-points by ROC curve, and evaluated BMRT HR-HPV for primary / secondary cervical cancer screening. RESULTS:The viral loads of HPV16/18, 12 other subtypes HR-HPV and 14 HR-HPV were statistically different in all grades of cervical lesions (P<0.05, among which HPV16, 33 and 58 showed the strongest relationship (P<0.01). The viral load of HR-HPV also increased with the grade of cervical lesions (P<0.05). The sensitivity for CIN2+ and CIN3+ of BMRT was comparable to Cobas (92.6% vs 94.3%, 100% vs 100%, P>0.05), specificity was higher than Cobas (84.8% vs 83.3%, 83.5% vs 82.0%, P<0.001). When using HPV16/18 viral load(log cut-point ≥3.2929), plus the viral-load of 12 other subtypes (log cut-point ≥3.9625) as secondary triage, compared with Cobas HPV16/18+ plus cytology ≥ASC-US as triage, the sensitivities for CIN2+ and CIN3+ were similar (P>0.05). However, the BMRT HR-HPV viral load combined with subtypes did not require cytology. CONCLUSION:BMRT is as sensitive as Cobas4800 for primary cervical cancer screening. BMRT HR-HPV viral load combined with subtypes can be used as a secondary strategy for cervical cancer screening, especially for areas with insufficient cytological resources.
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