An Integrated Approach for the Early Detection of Endometrial and Ovarian Cancers (Screenwide Study): Rationale, Study Design and Pilot Study
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SUBMITTER: Peremiquel-Trillas P
PROVIDER: S-EPMC9324683 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesThe aim of this study was to identify tumor-derived DNA from Papanicolaou (Pap) smear and plasma specimens collected from patients with endometrial cancer or atypical hyperplasia (EC/AH) or epithelial ovarian cancer (OC).MethodsTumor tissues, peripheral blood, and Pap smear samples were collected from patients with EC/AH and patients with epithelial OC. Somatic mutations of tumor specimens in EC/AH and OC were examined by whole-exome sequencing using a 127-driver gene panel from The Cancer Genome Atlas (TCGA). A nine-gene EC/AH panel and an eight-gene OC panel were established based on the identified significantly mutated genes in the EC/AH and OC tumor specimens. Circulating single-molecule amplification and resequencing technology (cSMART) was applied to evaluate somatic mutations in Pap smear DNA and plasma circulating cell-free DNA (ccfDNA) using the EC/AH and OC gene panels.ResultsIn EC/AH group, there existed 22 tumors and 14 of the 22 tumors contributed hot spot mutations for the EC/AH nine-gene panel. In the Pap smear subgroup, all 21 Pap smears tested positive. Nine out of 11 (81.8%) identified the same gene mutations with their matched tumors and the remaining 10 Pap smears all tested positive. In the plasma subgroup, 10 out of 26 (38.5%) plasmas tested positive. One out of 13 (7.7%) identified the same gene mutation with its matched tumor and 5 out of the remaining 13 plasmas (38.5%) tested positive. In OC group, there existed 17 tumors and 16 of the 17 tumors contributed hot spot mutations for the OC eight-gene panel. In the Pap smear subgroup, all 11 Pap smears tested positive. Five out of 10 (50.0%) identified the same gene mutations with their matched tumors and the remaining one Pap smear also tested positive. In the plasma subgroup, all 22 plasmas tested positive. Ten out of 14 (71.4%) identified the same gene mutation with their matched tumors and the remaining 4 plasmas all tested positive.ConclusionsTumor-derived DNA can be detected in Pap smears and plasmas from patients with EC/AH or epithelial OC. Using a small gene-panel, early detection of EC/AH and OC might be promising. However, the value of plasma ccfDNA for EC/AH requires further investigation.
| S-EPMC7768029 | biostudies-literature
Project description:Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.
| S-EPMC5354810 | biostudies-literature
Project description:Aberrant expression of cyclin-dependent kinase (CDK) inhibitors is implicated in the carcinogenesis of many cancers, including ovarian and endometrial cancers. We examined associations between CDK inhibitor expression, cancer risk factors, tumor characteristics, and survival outcomes among ovarian and endometrial cancer patients enrolled in a population-based case-control study. Expression (negative vs. positive) of three CDK inhibitors (p16, p21, and p27) and ki67 was examined with immunohistochemical staining of tissue microarrays. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarkers, risk factors, and tumor characteristics. Survival outcomes were only available for ovarian cancer patients and examined using Kaplan-Meier plots and Cox proportional hazards regression. Among ovarian cancer patients (n?=?175), positive p21 expression was associated with endometrioid tumors (OR?=?12.22, 95% CI?=?1.45-102.78) and higher overall survival (log-rank p?=?0.002). In Cox models adjusted for stage, grade, and histology, the association between p21 expression and overall survival was borderline significant (hazard ratio?=?0.65, 95% CI?=?0.42-1.05). Among endometrial cancer patients (n?=?289), positive p21 expression was inversely associated with age (OR???65?years of age?=?0.25, 95% CI?=?0.07-0.84) and current smoking status (OR: 0.33, 95% CI 0.15, 0.72) compared to negative expression. Our study showed heterogeneity in expression of cell-cycle proteins associated with risk factors and tumor characteristics of gynecologic cancers. Future studies to assess these markers of etiological classification and behavior may be warranted.
| S-EPMC4321403 | biostudies-literature
Project description:ObjectivesTo test two interventions to reduce interleukin (IL)-6 levels, an indicator of low-grade chronic inflammation and an independent risk factor for impaired mobility and slow walking speed in older adults.DesignThe ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot Study was a multicenter, double-blind, placebo-controlled randomized pilot trial of two interventions to reduce IL-6 levels.SettingFive university-based research centers.ParticipantsTarget enrollment was 300 men and women aged 70 and older with an average plasma IL-6 level between 2.5 and 30 pg/mL measured twice at least 1 week apart. Participants had low to moderate physical function, defined as self-reported difficulty walking one-quarter of a mile or climbing a flight of stairs and usual walk speed of less than 1 m/s on a 4-m usual-pace walk.InterventionParticipants were randomized to losartan, omega-3 fish oil (ω-3), combined losartan and ω-3, or placebo. Randomization was stratified depending on eligibility for each group. A titration schedule was implemented to reach a dose that was safe and effective for IL-6 reduction. Maximal doses were 100 mg/d for losartan and 2.8 g/d for ω-3.MeasurementsIL-6, walking speed over 400 m, physical function (Short Physical Performance Battery), other inflammatory markers, safety, tolerability, frailty domains, and maximal leg strength were measured.ResultsResults from the ENRGISE Pilot Study will provide recruitment yields, feasibility, medication tolerance and adherence, and preliminary data to help justify a sample size for a more definitive randomized trial.ConclusionThe ENRGISE Pilot Study will inform a larger subsequent trial that is expected to have important clinical and public health implications for the growing population of older adults with low-grade chronic inflammation and mobility limitations.
| S-EPMC5642998 | biostudies-literature
Project description:We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.
| S-EPMC6320220 | biostudies-literature
Project description:Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer.
| S-EPMC3293923 | biostudies-literature
Project description:Synchronous primary endometrial and ovarian cancers (SEOs) represent 10% of all endometrial and ovarian cancers and are assumed to develop as independent entities. We investigated the clonal relationship between endometrial and ovarian carcinomas in a large cohort classified as SEOs or metastatic disease (MD). The molecular profiles were compared to The Cancer Genome Atlas (TCGA) data to explore primary origin. Subsequently, the molecular profiles were correlated with clinical outcome. To this extent, a retrospective multicenter study was performed comparing patients with SEOs (n = 50), endometrial cancer with synchronous ovarian metastasis (n = 19) and ovarian cancer with synchronous endometrial metastasis (n = 20). Targeted next-generation sequencing was used, and a clonality index was calculated. Subsequently, cases were classified as POLE mutated, mismatch repair deficient (MMR-D), TP53-wild-type or TP53-mutated. In 92% of SEOs (46/50), the endometrial and concurrent ovarian carcinoma shared at least one somatic mutation, with a clonality index above 0.95, supporting a clonal origin. The SEO molecular profiles showed striking similarities with the TCGA endometrial carcinoma set. SEOs behaved distinctly different from metastatic disease, with a superior outcome compared to endometrial MD cases (p?<?0.001) and ovarian MD cases (p?<?0.001). Classification according to the TCGA identified four groups with different clinical outcomes. TP53 mutations and extra-utero-ovarian disease were independent predictors for poor clinical outcome. Concluding, SEOs were clonally related in an overwhelming majority of cases and showed a favorable prognosis. Their molecular profile implied a primary endometrial origin. TP53 mutation and extra-utero-ovarian disease were independent predictors for outcome, and may impact adjuvant systemic treatment planning.
| S-EPMC7317735 | biostudies-literature
Project description:IntroductionIn patients with transient thrombocytopenia being treated with high-dose chemotherapy followed by stem cell rescue-haematopoietic stem cell transplantation (HSCT), prophylactic transfusions are standard therapy to prevent bleeding. However, a recent multicentre trial suggests that prophylactic platelet transfusions in HSCT may not be necessary. Additionally, the potential overuse of platelet products places a burden on a scarce healthcare resource. Moreover, the benefit of prophylactic platelet transfusions to prevent clinically relevant haemorrhage is debatable. Current randomised data compare different thresholds for administering prophylactic platelets or prophylactic versus therapeutic platelet transfusions. An alternative strategy involves prescribing prophylactic antifibrinolytic agents such as tranexamic acid to prevent bleeding.Methods and analysisThis report describes the design of an open-labelled randomised pilot study comparing the prophylactic use of oral tranexamic acid with platelet transfusions in the setting of autologous HSCT. In 3-5 centres, 100 patients undergoing autologous HSCT will be randomly assigned to either a prophylactic tranexamic acid or prophylactic platelets bleeding prevention strategy-based daily platelet values up to 30 days post-transplant. The study will be stratified by centre and type of transplant. The primary goal is to demonstrate study feasibility while collecting clinical outcomes on (1) WHO and Bleeding Severity Measurement Scale (BSMS), (2) transplant-related mortality, (3) quality of life, (4) length of hospital stay, (5) intensive care unit admission rates, (6) Bearman toxicity scores, (7) incidence of infections, (8) transfusion requirements, (9) adverse reactions and (10) economic analyses.Ethics and disseminationThis study is funded by a peer-reviewed grant from the Canadian Institutes of Health Research (201 503) and is registered on Clinicaltrials.gov NCT02650791. It has been approved by the Ottawa Health Science Network Research Ethics Board. Study results will presented at national and international conferences. Importantly, the results of this trial will inform the feasibility and conduct of a larger study.Trial registration numberNCT02650791; Pre-results.
| S-EPMC5093651 | biostudies-literature
Project description:BackgroundWith the goal of realizing genome-based personalized healthcare, we have developed a biobank that integrates personal health, genome, and omics data along with biospecimens donated by volunteers of 150,000. Such a large-scale of data integration involves obvious risks of privacy violation. The research use of personal genome and health information is a topic of global discussion with regard to the protection of privacy while promoting scientific advancement. The present paper reports on our plans, current attempts, and accomplishments in addressing security problems involved in data sharing to ensure donor privacy while promoting scientific advancement.MethodsBiospecimens and data have been collected in prospective cohort studies with the comprehensive agreement. The sample size of 150,000 participants was required for multiple researches including genome-wide screening of gene by environment interactions, haplotype phasing, and parametric linkage analysis.ResultsWe established the T ohoku M edical M egabank (TMM) data sharing policy: a privacy protection rule that requires physical, personnel, and technological safeguards against privacy violation regarding the use and sharing of data. The proposed policy refers to that of NCBI and that of the Sanger Institute. The proposed policy classifies shared data according to the strength of re-identification risks. Local committees organized by TMM evaluate re-identification risk and assign a security category to a dataset. Every dataset is stored in an assigned segment of a supercomputer in accordance with its security category. A security manager should be designated to handle all security problems at individual data use locations. The proposed policy requires closed networks and IP-VPN remote connections.ConclusionThe mission of the biobank is to distribute biological resources most productively. This mission motivated us to collect biospecimens and health data and simultaneously analyze genome/omics data in-house. The biobank also has the mission of improving the quality and quantity of the contents of the biobank. This motivated us to request users to share the results of their research as feedback to the biobank. The TMM data sharing policy has tackled every security problem originating with the missions. We believe our current implementation to be the best way to protect privacy in data sharing.
| S-EPMC5501115 | biostudies-literature
Project description:Papanicolaou (Pap) smears have revolutionized the management of patients with cervical cancers by permitting the detection of early, surgically curable tumors and their precursors. In recent years, the traditional Pap smear has been replaced by a liquid-based method, which allows not only cytologic evaluation but also collection of DNA for detection of human papillomavirus, the causative agent of cervical cancer. We reasoned that this routinely collected DNA could be exploited to detect somatic mutations present in rare tumor cells that accumulate in the cervix once shed from endometrial or ovarian cancers. A panel of genes that are commonly mutated in endometrial and ovarian cancers was assembled with new whole-exome sequencing data from 22 endometrial cancers and previously published data on other tumor types. We used this panel to search for mutations in 24 endometrial and 22 ovarian cancers and identified mutations in all 46 samples. With a sensitive massively parallel sequencing method, we were able to identify the same mutations in the DNA from liquid Pap smear specimens in 100% of endometrial cancers (24 of 24) and in 41% of ovarian cancers (9 of 22). Prompted by these findings, we developed a sequence-based method to query mutations in 12 genes in a single liquid Pap smear specimen without previous knowledge of the tumor's genotype. When applied to 14 samples selected from the positive cases described above, the expected tumor-specific mutations were identified. These results demonstrate that DNA from most endometrial and a fraction of ovarian cancers can be detected in a standard liquid-based Pap smear specimen obtained during routine pelvic examination. Although improvements need to be made before applying this test in a routine clinical manner, it represents a promising step toward a broadly applicable screening methodology for the early detection of gynecologic malignancies.
| S-EPMC3757513 | biostudies-literature