The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer.
BACKGROUND: Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients. RESULTS: The WIDTM-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case-control) and predictive setting (nested case-control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WIDTM-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WIDTM-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt-) index sample who were diagnosed with CIN3 1-4 years after sample donation. CONCLUSION: We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WIDTM-qCIN, a PCR-based DNAme test. The WIDTM-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case-control settings and future studies will assess performance and generalisability in a randomised controlled trial.
- MeSH
- Alphapapillomavirus * MeSH
- časná detekce nádoru MeSH
- dospělí MeSH
- dysplazie děložního hrdla * diagnóza genetika MeSH
- infekce papilomavirem * diagnóza genetika MeSH
- lidé MeSH
- metylace DNA MeSH
- nádory děložního čípku * diagnóza genetika MeSH
- Papillomaviridae genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival. METHODS: We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86). RESULTS: We describe the Women's cancer risk IDentification - quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12. In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology. CONCLUSION: The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits.
- MeSH
- časná detekce nádoru metody MeSH
- epigeneze genetická MeSH
- infekce papilomavirem * diagnóza MeSH
- lidé MeSH
- nádory děložního čípku * diagnóza genetika MeSH
- nádory endometria * diagnóza genetika MeSH
- třídění pacientů MeSH
- vaginální stěr metody MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.
- MeSH
- cervix uteri cytologie metabolismus MeSH
- CpG ostrůvky MeSH
- epigenom MeSH
- epigenomika metody MeSH
- epitelové buňky metabolismus MeSH
- lidé MeSH
- metylace DNA * MeSH
- mutace MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádory prsu genetika metabolismus MeSH
- prognóza MeSH
- prsy cytologie metabolismus MeSH
- ROC křivka MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk-predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing.
- MeSH
- epigenomika trendy MeSH
- genom lidský genetika MeSH
- hodnocení rizik * MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- nádory epidemiologie genetika MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
To contribute to improving quality of laboratory services for effective surveillance and monitoring of HPV vaccination impact, WHO has initiated a global HPV LabNet. The LabNet tasks are to facilitate implementation of standardized, state-of-the-art HPV laboratory methods by introducing international standards, proficiency testing reagents/methods, standard operating procedures and quality assurance (QA) programs in order to make results comparable across laboratories worldwide. The LabNet is also intended to form the basis for development of a global network for HPV surveillance by using standardized and harmonized laboratory methodologies in order to provide sound data to policy-makers. The LabNet is composed of 2 global reference laboratories (GRL) and 1-2 regional reference laboratories (RRL) in each WHO region. The GRL provide coordination of the network, lead development of QA programs and perform confirmatory testing of samples from regions. The GRL also oversee the HPV prevalences and vaccination impact worldwide through collaboration with RRL. Eventually, a formalized global HPV laboratory network will provide HPV surveillance and vaccination impact evaluation in an internationally harmonized way. Effective HPV surveillance programs will be an essential component of appropriately implemented HPV vaccination programs. Such surveillance should be based on internationally standardised and quality assured laboratory methods in order to make results comparable across laboratories in the world.
- MeSH
- diagnostické techniky molekulární normy využití MeSH
- infekce papilomavirem diagnóza imunologie MeSH
- klinické laboratorní techniky metody přístrojové vybavení využití MeSH
- lidé MeSH
- plošný screening metody normy využití MeSH
- referenční standardy MeSH
- řízení kvality MeSH
- sérologie metody normy MeSH
- směrnice jako téma MeSH
- Světová zdravotnická organizace MeSH
- vakcíny proti papilomavirům MeSH
- Check Tag
- lidé MeSH
