From Case Reports to Molecular Insight: Examining the Outcomes and Underlying Mechanisms of Squamous Cell Carcinoma in Breast Implant Patients-A Systematic Review.

There is extensive coverage in the existing literature on implant-associated lymphomas like anaplastic large-cell lymphoma, but breast implant-associated squamous cell carcinoma (BIA-SCC) has received limited scholarly attention since its first case in 1992. Thus, this study aims to conduct a qualitative synthesis focused on the underexplored association between breast implants and BIA-SCC. A systematic review was conducted utilizing the PubMed, Web of Science, and Cochrane databases to identify all currently reported cases of BIA-SCC. Additionally, a literature review was performed to identify potential biochemical mechanisms that could lead to BIA-SCC. Studies were vetted for quality using the NIH quality assessment tool. From an initial pool of 246 papers, 11 met the quality criteria for inclusion, examining a total of 14 patients aged between 40 and 81 years. BIA-SCC was found in a diverse range of implants, including those with smooth and textured surfaces, as well as those filled with saline and silicone. The condition notably manifested a proclivity for aggressive clinical progression, as evidenced by a mortality rate approximating 21.4% within a post-diagnostic interval of six months. Our literature review reveals that chronic inflammation, driven by various external factors such as pathogens and implants, can initiate carcinogenesis through epigenetic modifications and immune system alterations. This includes effects from exosomes and macrophage polarization, showcasing potential pathways for the pathogenesis of BIA-SCC. The study highlights the pressing need for further investigation into BIA-SCC, a subject hitherto inadequately addressed in the academic sphere. This necessitates the urgency for early screening and intervention to improve postoperative outcomes. While the review is confined by its reliance on case reports and series, it serves as a valuable reference for future research endeavors.

Cigarette Smoking and E-cigarette Use Induce Shared DNA Methylation Changes Linked to Carcinogenesis.

Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci [cytosine-phosphate-guanine sites (CpG)] clustered into four functional groups, including detoxification or growth signaling, based on cell type and anatomic site. Loci hypermethylated in buccal epithelial cells of smokers associated with NOTCH1/RUNX3/growth factor receptor signaling also exhibited elevated methylation in cancer tissue and progressing lung carcinoma in situ lesions, and hypermethylation of these sites predicted lung cancer development in buccal samples collected from smokers up to 22 years prior to diagnosis, suggesting a potential role in driving carcinogenesis. Alarmingly, these CpGs were also hypermethylated in e-cigarette users with a limited smoking history. This study sheds light on the cell type-specific changes to the epigenetic landscape induced by smoking-related products. SIGNIFICANCE: The use of both cigarettes and e-cigarettes elicits cell- and exposure-specific epigenetic effects that are predictive of carcinogenesis, suggesting caution when broadly recommending e-cigarettes as aids for smoking cessation.

Correlation of toxoplasmosis with small­for­gestational­age newborns.

BACKGROUND: Toxoplasma gondii infection in pregnant women could lead to significant changes during the pregnancy, affect the outcomes of pregnancy and the timing of labour. Small­for­gestational­age (SGA) newborns are defined by birthweight below the 10th percentile for gestational age. We tested an association between latent toxoplasmosis in pregnant women and deliveries of SGA babies. MATERIAL AND METHODS: For testing, we included 1,647 women who gave birth to a singleton baby at ≥ 37 weeks of gestation. The complement-fixation test (CFT) and enzyme-linked immunosorbent assay (ELISA) tests for IgG and IgM were used. The latent form of toxoplasmosis was defined as a CFT titre of 1:8 or higher, together with index positivity IgG ELISA > 1.1 and negative IgM. RESULTS: There were 406 (24.7 %) women positive, and 1,241 (75.3 %) women negative for latent toxoplasmosis. Of all deliveries. 190 were SGA­positive and 1,457 were SGA­negative. Our study found a statistically significant association between latent toxoplasmosis and SGA foetuses born at term. The Pearson chi-square model was statistically significant (χ2(1) = 7.365, p = .007). The odds ratio was 1.567. CONCLUSION: Pregnant women with latent toxoplasmosis giving birth at ≥ 37 weeks of gestation have a 1.567 times higher risk of delivering an SGA baby (Tab. 2, Fig. 1, Ref. 30).

Plasma cell-free DNA methylation analysis for ovarian cancer detection: Analysis of samples from a case-control study and an ovarian cancer screening trial.

Analysis of cell-free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell-free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case-control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%-99.9%). High-risk cancers were detected with a sensitivity of 80% (56.3%-94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%-99.9%) for high-risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%-100.0%). We detected 27.3% (6.0%-61.0%) of high-risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%-70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high-risk populations, but future large-scale prospective studies will be required to validate current findings.

Risk Factors for the Anal and Oral Human Papillomavirus (HPV) Infections among Women with Severe Cervical Lesions: A Prospective Case-Control Study.

The carcinogenicity of HPV infection in the anogenital and oropharyngeal regions is broadly accepted. The aim of the study was to define risk factors for anal and oral HPV infections in high-risk patients with biopsy-proven severe cervical lesions (CIN2+). Altogether immunocompetent 473 females with CIN2+ were categorized into the study group and another 245 women into the control group. The strongest risk factor for anal HPV infection was the presence of cervical HPV infection (p < 0.001). Furthermore, ten or more lifetime sexual partners (p = 0.013), a sexual non-coital contact with the anal area (p < 0.001), and actively practicing anal-penetrative intercourse (p < 0.001) were significantly associated with anal HPV. A history of genital warts in the woman (p = 0.010) and the presence of genital warts in the male partner (p = 0.029) were found statistically significant for the risk of oral HPV infection. Our data suggest that the presence of HPV infection, especially high-risk genotypes, in one anatomical site poses the greatest risk for HPV infection in another anatomical site. The cervix is the main reservoir of infection, but the risk factors for anal and oral HPV infections are dissimilar according to different anatomical distances and more complex routes of transmission.

Implementation of the ERAS protocol in gynecology and oncogynecology - evaluation of a pilot study.

OBJECTIVE: To describe the implementation process and evaluate the success of compliance with the recommended ERAS protocol in the Czech healthcare system. METHODS: The study included 163 patients from March to September 2022, a total of 7 months. Patients were divided into three groups according to the type of surgery. Clinical protocol: Oncogynecology, hysterectomy and laparoscopy. The implementation was realized in three phases (preparation, implementation of the protocol itself and evaluation). RESULTS AND CONCLUSIONS: The cumulative adherence rate was 90% or more in all three groups. Based on the pilot results at our department, we evaluated the ERAS concept as a well-implemented tool for gynaecological departments in the Czech healthcare system.

DNA methylation at quantitative trait loci (mQTLs) varies with cell type and nonheritable factors and may improve breast cancer risk assessment.

To individualise breast cancer (BC) prevention, markers to follow a person's changing environment and health extending beyond static genetic risk scores are required. Here, we analysed cervical and breast DNA methylation (n = 1848) and single nucleotide polymorphisms (n = 1442) and demonstrate that a linear combination of methylation levels at 104 BC-associated methylation quantitative trait loci (mQTL) CpGs, termed the WID™-qtBC index, can identify women with breast cancer in hormone-sensitive tissues (AUC = 0.71 [95% CI: 0.65-0.77] in cervical samples). Women in the highest combined risk group (high polygenic risk score and WID™-qtBC) had a 9.6-fold increased risk for BC [95% CI: 4.7-21] compared to the low-risk group and tended to present at more advanced stages. Importantly, the WID™-qtBC is influenced by non-genetic BC risk factors, including age and body mass index, and can be modified by a preventive pharmacological intervention, indicating an interaction between genome and environment recorded at the level of the epigenome. Our findings indicate that methylation levels at mQTLs in relevant surrogate tissues could enable integration of heritable and non-heritable factors for improved disease risk stratification.

Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study.

PURPOSE: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

BRCA mutation carriers suffering from ovarian cancer as a model for treatment decision in higher lines - Place for platinum reinduction.

Context: Ovarian carcinoma is a malignancy with the highest mortality among gynecological cancers. Mutations in BRCA1/2 genes are believed to be a favorable prognostic factor and that, in general, the biological behavior of ovarian cancer in BRCA-positive individuals differs from others. However, some clinically relevant issues (i.e., prediction of response to chemotherapy and treatment of platinum-resistant BRCA-positive patients) remain unclear. Aims: (1) The aim of this study was to examine the prevalence of germline BRCA mutations in unselected recurrent ovarian cancer patient population, (2) analyze whether biological behavior of BRCA-positive tumors differs from others, and (3) analyze the effect of platinum reinduction in platinum-resistant BRCA-positive patients. Settings and Design: This was a single-institution retrospective analysis. Subjects and Methods: Consecutive recurrent ovarian cancer patients from years 2012 to 2020 were included; their BRCA1/2 mutational status was analyzed and correlated with progression-free survival (PFS), type of treatment, and response to treatment. Statistical Analysis Used: Statistical significance of differences between and among patients was tested for continuous variables by the Mann-Whitney U-test or the Kruskal-Wallis test; a maximum likelihood Chi-square test was used for categorical variables. Results: Two hundred and forty-three recurrent ovarian cancer patients were included. The median follow-up was 37 months. Pathogenic mutation in BRCA1 or BRCA2 gene was found in 18.1% of patients. There was no difference in PFS comparing BRCA-positive to BRCA-negative patients (median PFS: 10.2 vs. 10.1 months, P = 0.874); there was a difference in PFS comparing BRCA-negative versus BRCA-positive platinum-sensitive patients (9.4 vs. 14.3 months, P = 0.002). BRCA-positive platinum-resistant patients reinduced with platinum achieved a median PFS of 8 months (compared to those receiving nonplatinum treatment, median PFS: 4 months, P = 0.062). Conclusions: Germline BRCA mutations are not exclusive to platinum-sensitive ovarian cancer patients; even in platinum-resistant patients, mutation can be detected. We found no difference in PFS for platinum-sensitive BRCA-positive and BRCA-negative patients. Platinum reinduction may be considered for BRCA-positive platinum-resistant ovarian cancer patients to prolong PFS. Even these data describe only a small population, it supports the clinical practice of platinum-based chemotherapy use in platinum-resistant BRCA-positive patients.

Germline multigene panel testing of patients with endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

Severe hepatic rupture in HELLP syndrome.

OBJECTIVE: To describe the multidisciplinary approach that led to the successful management of severe hepatic rupture in HELLP syndrome at 35 weeks of gestation. CASE REPORT: The clinical course and management procedure of a 34-year-old female patient with ruptured liver due to HELLP syndrome, who was admitted with symptoms lasting about 4 hours (pain in the right hypochondrium, nausea, vomiting, flashes before the eyes) are described in the form of a case report. An acute caesarean section was performed, during which a rupture of the subcapsular hematoma of the liver was dia-gnosed. Subsequently, the patient developed hemorrhagic shock and coagulopathy with the need for repeated surgical revisions of bleeding from the rupture of the liver. CONCLUSION: Subcapsular hematoma rupture is a rare but serious complication of HELLP syndrome. This case shows the importance of early dia-gnosis and prompt termination of pregnancy in the shortest possible time in pregnancy after 34 weeks. The most fundamental factor that influenced the patient's outcome and morbidity was the management of multidisciplinary cooperation and the correct timing of individual steps.

Anti-Müllerian hormone - clinical use and future possibilities.

Anti-Müllerian hormone (AMH) is a protein produced already in human fetus. It has an essential role in the differentiation of the reproductive tract, regulation of the ovaries and testes. The determination of serum AMH levels is used in clinical practice. Today, especially in reproductive medicine in the assessment of ovarian reserve and in the prediction of the response to ovarian stimulation. However, in young cancer patients, it can also predict the risk of ovarian failure after anticancer treatment. It finds further use in pediatric endocrinology in the diagnosis of sexual differentiation disorders. In oncology, it is used as a tumor marker for monitoring patients with granulosa tumors. In the future, however, it is also promising to use the knowledge of AMH function for the treatment of gynecological as well as other solid malignancies expressing a tissue-specific receptor for AMH.

Hypoxia as a potential cause of dyspareunia.

Dyspareunia is genital pain before, during or after penile-vaginal sexual intercourse. The prevalence of dyspareunia ranges from 8 to 22%. Sexual intercourse concomitant with a pelvic organic lesion is likely to cause pain in most cases. However, in these cases, the pain depends not only on sexual intercourse. In its basic definition, dyspareunia in women is considered an idiopathic affection without a typical organic constitution. It is only present with penile-vaginal penetration. Long-term hypoxia in perineal muscles can cause muscle and perimuscular changes, leading to chronic pain not sufficiently responding to standard therapy. During the entrance examination to our previous study on dyspareunia, we noted significantly lower pulse oximetry levels in the perineal area of affected women. We aimed to compare pulse oximetry oxygen saturation (SpO2) of dyspareunia-affected women to healthy, pain-free women. A retrospective study was performed. The study participants were women who had participated in our previously published study on dyspareunia. This retrospective study was approved by the Ethical Committee. The study included 62 women: 31 dyspareunia-affected women in the treatment group and 31 healthy women in the control group. METHOD: During their examinations, women in the dyspareunia and control groups were measured for SpO2. The procedure was performed in the vulvo-perineal rear region, involving the commissure and the bulbospongiosus muscle. Median and mean SpO2 were compared between the treatment and control groups. Testing for sample size accuracy was performed retroactively. RESULTS: There were 31 participants in each group. The SpO2 data were skewed and did not follow a Gaussian distribution. The Mann-Whitney U test was run to determine differences in perineum oximetry between the treatment group and controls. The median SpO2 was 91 in the treatment group and 92 in the control group. This difference was statistically significant, p = 0.002. Sample size accuracy was assured by post hoc calculation. CONCLUSIONS: Idiopathic dyspareunia is inherent in cohabitation muscle pain that standard therapy could not explain nor treat. We detected clinically meaningfully decreased levels of SpO2 in affected patients. We compared pelvic oximetry between dyspareunia-affected women in the treatment and control groups. This comparison showed significant hypoxia in the perineal muscle area (p = 0.002). Our results may help us understand the source of this pain and guide treatment accordingly.

The WID-EC test for the detection and risk prediction of endometrial cancer.

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.

The WID-qEC test: Performance in a hospital-based cohort and feasibility to detect endometrial and cervical cancers.

The majority of endometrial and cervical cancers present with abnormal vaginal bleeding but only a small proportion of women suffering from vaginal bleeding actually have such a cancer. A simple, operator-independent and accurate test to correctly identify women presenting with abnormal bleeding as a consequence of endometrial or cervical cancer is urgently required. We have recently developed and validated the WID-qEC test, which assesses DNA methylation of ZSCAN12 and GYPC via real-time PCR, to triage women with symptoms suggestive of endometrial cancer using ThinPrep-based liquid cytology samples. Here, we investigated whether the WID-qEC test can additionally identify women with cervical cancer. Moreover, we evaluate the test's applicability in a SurePath-based hospital-cohort by comparing its ability to detect endometrial and cervical cancer to cytology. In a set of 23 cervical cancer cases and 28 matched controls the receiver operating characteristic (ROC) area under the curve (AUC) is 0.99 (95% confidence interval [CI]: 0.97-1.00) with a sensitivity and specificity of 100% and 92.9%, respectively. Amongst the hospital-cohort (n = 330), the ROC AUC is 0.99 (95% CI: 0.98-1) with a sensitivity and specificity of 100% and 82.5% for the WID-qEC test, respectively, and 33.3% and 96.9% for cytology (considering PAP IV/V as positive). Our data suggest that the WID-qEC test detects both endometrial and cervical cancer with high accuracy.

DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID™-qCIN test.

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 WID™-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 WID™-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 WID™-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 WID™-qCIN, a PCR-based DNAme test. The WID™-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.

A Simple Cervicovaginal Epigenetic Test for Screening and Rapid Triage of Women With Suspected Endometrial Cancer: Validation in Several Cohort and Case/Control Sets.

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.

The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples.

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.

The DNA methylome of cervical cells can predict the presence of ovarian cancer.

The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women's risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention.