Ovarian Cancer Histotypes Research Articles

Comprehensive genomic profiling in ovarian cancer histotypes: Biomarker prevalence and real-world prognosis

Comprehensive genomic profiling in ovarian cancer histotypes: Biomarker prevalence and real-world prognosis

Endometriosis Typology and Ovarian Cancer Risk

Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described. To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis. Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other. Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations. In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]). Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.

Ovarian carcinosarcoma is highly aggressive compared to other ovarian cancer histotypes

BackgroundOvarian carcinosarcoma (OCS) is an unusual ovarian cancer type characterized by distinct carcinomatous and sarcomatous components. OCS has been excluded from many of the pan-histotype studies of ovarian carcinoma, limiting our understanding of its behavior.MethodsWe performed a multi-cohort cross-sectional study of characteristics and outcomes in ovarian cancer patients from Scotland (n=2082) and the Surveillance, Epidemiology and End Results Program (SEER, n=44946) diagnosed with OCS or one of the other major histotypes: high grade serous (HGSOC), endometrioid (EnOC), clear cell (CCOC), mucinous (MOC) or low grade serous ovarian carcinoma (LGSOC). Differences in overall survival were quantified using Cox regression models to calculate hazard ratios (HR).ResultsAcross both cohorts, OCS patients were significantly older at diagnosis compared to all other histotypes (median age at diagnosis 69 and 67 in Scottish and SEER cohorts) and demonstrated the shortest survival time upon univariable analysis. Within the Scottish cohort, 59.3% and 16.9% of OCS patients presented with FIGO stage III and IV disease, respectively; this was significantly higher than in EnOC, CCOC or MOC (P<0.0001 for all), but lower than in HGSOC (P=0.004). Multivariable analysis accounting for other prognostic factors identified OCS as independently associated with significantly shorter survival time compared to HGSOC, EnOC, LGSOC and MOC in both the Scottish (multivariable HR vs OCS: HGSOC 0.45, EnOC 0.39, LGSOC 0.26, MOC 0.43) and SEER cohorts (multivariable HR vs OCS: HGSOC 0.59, EnOC 0.34, LGSOC 0.30, MOC 0.81). Within the SEER cohort, OCS also demonstrated shorter survival compared to CCOC (multivariable HR 0.63, 95% CI 0.58-0.68), but this was not replicated within the Scottish cohort (multivariable HR for CCOC: 1.05, 95% CI 0.74-1.51). Within early-stage disease specifically (FIGO I-II or SEER localized stage), OCS was associated with the poorest survival of all histotypes across both cohorts. In the context of late-stage disease (FIGO III-IV or SEER distant stage), OCS, MOC and CCOC represented the histotypes with poorest survival.ConclusionOCS is a unique ovarian cancer type that affects older women and is associated with exceptionally poor outcome, even when diagnosed at earlier stage. New therapeutic options are urgently required to improve outcomes.

VOLTA: an enVironment-aware cOntrastive ceLl represenTation leArning for histopathology

In clinical oncology, many diagnostic tasks rely on the identification of cells in histopathology images. While supervised machine learning techniques necessitate the need for labels, providing manual cell annotations is time-consuming. In this paper, we propose a self-supervised framework (enVironment-aware cOntrastive cell represenTation learning: VOLTA) for cell representation learning in histopathology images using a technique that accounts for the cell’s mutual relationship with its environment. We subject our model to extensive experiments on data collected from multiple institutions comprising over 800,000 cells and six cancer types. To showcase the potential of our proposed framework, we apply VOLTA to ovarian and endometrial cancers and demonstrate that our cell representations can be utilized to identify the known histotypes of ovarian cancer and provide insights that link histopathology and molecular subtypes of endometrial cancer. Unlike supervised models, we provide a framework that can empower discoveries without any annotation data, even in situations where sample sizes are limited.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5×10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (pvalue <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma

BackgroundLow grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies. MethodsWe performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines. Results16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy. ConclusionDasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.

Abstract 2195: Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study

Abstract Introduction: Ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) are the most fatal gynecologic cancers. Thus, it is imperative to identify strategies that can reduce the risk of the disease. Several contraceptive methods have been shown to be associated with a reduced risk of ovarian cancer, including combined oral contraceptives, injectable progestins, and tubal ligation. However, the use of these contraceptive methods has been decreasing in the U.S., with a growing preference for intrauterine devices (IUDs) for pregnancy prevention. Previous case-control studies on the association between IUD use and ovarian cancer risk have found inconsistent results. Notably, previous studies had small sample sizes and did not restrict to invasive epithelial tumors. The current analysis assessed the association between IUD use and risk of invasive epithelial ovarian cancer in a large population-based case-control study. Methods: This analysis used data from 1,713 people diagnosed with primary invasive epithelial ovarian cancer (cases) and 2,348 cancer-free people (controls) participating in a case-control study conducted in Los Angeles, CA from 1992-2010. The study consisted of four waves of recruitment with similar enrollment and data collection methods. Logistic regression models were fit to assess the association between IUD use and risk of invasive epithelial ovarian cancer. All models were adjusted for age, race/ethnicity, education, first-degree family history of ovarian cancer, endometriosis, body mass index, duration of combined oral contraceptive use, parity, duration of breastfeeding, tubal ligation, and study wave. Heterogeneity across the study waves and the ovarian cancer histotypes was evaluated using standard meta-analysis techniques. Results: There was no statistically significant association between IUD use and risk of invasive epithelial ovarian cancer (odds ratio=1.09, 95% confidence interval 0.93-1.28). This result was consistent across the study waves and the ovarian cancer histotypes (p-values for heterogeneity&amp;gt;0.05). Conclusion: IUD use was not associated with the risk of invasive epithelial ovarian cancer. Analysis by IUD type (i.e., hormone-releasing vs copper IUDs) was not possible in this study as these data were not collected. Future research should examine whether the type of IUD (i.e. copper versus hormone-releasing) may have different effects on risk of ovarian cancer. Citation Format: Minh Tung Phung, Yuting Wang, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2195.

Abstract A042: History of infertility and risk of ovarian cancer in the women’s health initiative

Abstract Background: Given the consistent relationship between reproductive factors (e.g. parity) and risk of epithelial ovarian cancer, several studies have investigated the relation between infertility and ovarian cancer with conflicting results. Prior research has suggested differences in risk by specific infertility subgroups, which may have contributed to the conflicting findings. Further, few studies examined associations by ovarian cancer histotypes or were able to disentangle the influence of infertility vs. fertility treatment. Differences across studies could also have been influenced by different study populations (e.g., population-based vs. clinical population/registry of in-vitro fertilization [IVF]) and lack of consistent statistical control for important confounding factors including nulliparity, number of pregnancies, and age at first pregnancy. Finally, prior prospective studies have had limited follow-up, thus not capturing cancers that occur after menopause and which may have different risk factor profiles. Our objective was to determine the association between history of infertility and risk of postmenopausal ovarian cancer in a population that had not received treatment with IVF. Methods: We utilized the Women’s Health Initiative (n=114,761) with over 25 years of follow-up. At study baseline participants were asked whether they had ever tried to become pregnant for more than one year without becoming pregnant and whether a reason was found. Cox proportional hazards models were used to calculate the hazard ratios (HRs) of incident ovarian cancer comparing participants with a history of infertility to parous participants without infertility. Logistic regression models were used to calculate odds ratios (OR) for prevalent ovarian cancer at study baseline. Results: Approximately 16% of participants reported a history of infertility. 1,376 participants reported prevalent ovarian cancer at study baseline and 852 cases of ovarian cancer were diagnosed during study follow-up. In the prospective analyses, no statistically significant association was observed between infertility and risk of ovarian cancer overall (HR=1.16; 95% CI=0.98-1.37), by histotype, or with any specific infertility diagnoses. When prevalent ovarian cancer was examined, those reporting a history of infertility had a greater odds of ovarian cancer diagnosis (1.34; 95% CI=1.13-1.58) at WHI cohort baseline. This association was present for most infertility diagnoses with the strongest associations for hormonal/ovulatory (OR=1.97;95% CI=1.24-3.12), tubal/uterine factor (OR=1.63; 95% CI=1.15-2.31), and male factor (OR=1.71; 95% CI=1.19-2.47) infertility. Conclusions: We observed no significant association between infertility history and incident ovarian cancer in our population of postmenopausal participants. An association between infertility and ovarian cancer was present when prevalent ovarian cancer cases were examined, consistent with prior analyses that show stronger associations between ovarian cancer risk factors and ovarian cancer among younger women. Citation Format: Holly Harris, Kimberly Lind, Cynthia Thomson, Nazmus Saquib, Aladdin Shadyab, Peter Schnatz, Rogelio Robles-Morales, Lihong Qi, Howard Strickler, Denise Roe, Leslie Farland. History of infertility and risk of ovarian cancer in the women’s health initiative [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A042.

Histologic Subtypes in Endometriosis-Associated Ovarian Cancer and Ovarian Cancer Arising in Endometriosis: A Systematic Review and Meta-Analysis

The definition of the association between ovarian cancer and endometriosis was first reported by Sampson in 1925. He identified the following criteria: (a) clear evidence of endometriosis in proximity to the tumour, (b) exclusion of a metastatic tumour to the ovary, (c) presence of tissue resembling endometrial stroma surrounding epithelial glands. The naming of these cancers is “endometriosis-associated ovarian cancer” (EAOC). Scott proposed an additional stringent criterion: evidence of histological transition from endometriosis to cancer is to define “ovarian cancer arising in endometriosis” (OCAE). The aim of this systematic review is to analyse the distribution of different ovarian cancer histotypes in EAOC and OCAE to understand their similarities and differences. A total of 31 studies were included. Four studies added data for both EAOC and OCAE. Twenty-three studies were selected for EAOC, with a total of 800 patients, and 12 studies were selected for OCAE, with a total of 375 patients. The results show no significant differences in the distribution of histotypes in the two populations analysed. Clear cell carcinoma (CCC) and endometrioid carcinoma (EC) were the most common subtypes and were less frequent in EAOC compared to OCAE; the odd ratios were 0.58 (0.26–1.29) and 0.65 (0.33–1.26) respectively, although the difference was not statistically significant. The other histotypes were present in small proportions. This analysis shows that the histological profiles of EAOC and OCAE are similar, suggesting a similar aetiopathological mechanism, which requires further research to investigate whether EAOC and OCAE may be in the same way but at different points of the process to malignancy or have different pathways of progression to malignancy.

Abstract B004: Precision medicine opportunities: uniformity across stromal components of ovarian cancer histotype contrasts heterogeneous disease

Abstract Introduction: Clinical and molecular heterogeneity are hallmarks that distinguish each of the five major ovarian carcinoma histotypes. High-grade serous ovarian carcinomas (HGSC) are by far the most prominent type (70%) and thought to arise from the fallopian tube and appear driven by DNA damage phenotypes with high levels of copy number change. The second and third most common types are clear cell (CCOC) and endometrioid (ENOC) (20-25%), both of which are known to originate from endometriosis, with emerging evidence of molecular substructure in each type. Using an-omics approaches we regulatory elements and resulting expression signatures across tumor-epithelium and stromal compartments of these three most common histologies. Methods: We performed compartment-specific laser-capture microdissection and conducted methylation and gene expression sequencing on 75 fresh frozen primary tumor samples from each of CCOC, HGSC, ENOC (20 per subtype). Immunohistochemistry was used to determine the state of common molecular markers (e.g., WT1, p53, HNF1B, ER, PR). Results Preliminary RNA-Seq data complements previous findings in the bulk tissue analysis: WT1 is highly overexpressed in HGSC, HFN1B is overexpressed in CCOC and high ESR1-levels and low HAVCR1 expression can be found comparing ENOC with CCOC tissue. In the stroma differential gene expression overall had smaller logFC, however, CLCN2 was low in CCOC and HGSC compared to ENOC and MYH2/14 was significantly higher in both endometriosis-associated types. Estimations of immune cell infiltration (CIBERSORT) showed a gradual immune response between compartments and histotypes, with highest involvement seen in (stromal) HGSC. Beside multiple collagen genes, THBS1 has been highly expressed in stroma across all histotypes which can be targeted with approved drugs. Curiously, the epigenetic analysis showed that there is little variation in the stroma across these histotype, with similar to what was seen in the transcriptome. Conclusion: The tumor epithelial compartments of HGSC, ENOC, and CCOC showed unique regulatory signatures, consistent with previous bulk analysis. In contrast we observed relatively little heterogeneity in the stromal compartments, suggesting the tumor associated fibroblast component in particular may play a passive role in tumor progression and may contribute less to observed regulatory signatures. Nonetheless, this uniformity in gene expression may be exploited with pan-ovarian carcinoma treatment strategies. Citation Format: Karolin Heinze, Ian Beddows, Bianca Ribeiro de Souza, Hui Shen, Martin Koebel, Michael S. Anglesio. Precision medicine opportunities: uniformity across stromal components of ovarian cancer histotype contrasts heterogeneous disease [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B004.

Exploring the tumor micro-environment in primary and metastatic tumors of different ovarian cancer histotypes.

Ovarian cancer is a highly heterogeneous disease consisting of at least five different histological subtypes with varying clinical features, cells of origin, molecular composition, risk factors, and treatments. While most single-cell studies have focused on High grade serous ovarian cancer, a comprehensive landscape of the constituent cell types and their interactions within the tumor microenvironment are yet to be established in the different ovarian cancer histotypes. Further characterization of tumor progression, metastasis, and various histotypes are also needed to connect molecular signatures to pathological grading for personalized diagnosis and tailored treatment. In this study, we leveraged high-resolution single-cell RNA sequencing technology to elucidate the cellular compositions on 21 solid tumor samples collected from 12 patients with six ovarian cancer histotypes and both primary (ovaries) and metastatic (omentum, rectum) sites. The diverse collection allowed us to deconstruct the histotypes and tumor site-specific expression patterns of cells in the tumor, and identify key marker genes and ligand-receptor pairs that are active in the ovarian tumor microenvironment. Our findings can be used in improving precision disease stratification and optimizing treatment options.

ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by epigenetic modification

High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part. ALDH1A3 (aldehyde dehydrogenase 1 family member A3) is a key enzyme for acetyl-CoA production involving aggressive behaviors of cancers. However, ALDH1A3's effects and molecular mechanisms in HGSOC remain to be clarified. Using RNA-seq and publicly available datasets, ALDH1A3 was found to be highly expressed in HGSOC, and associated with poor survival. Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin. ALDH1A3 expression in HGSOC cells was found to be increased by hypoxia, but decreased by HIF-1α inhibitor KC7F2. The dual-luciferase reporter assay showed that the increased transcriptional activity of ALDH1A3 induced by HIF-1α overexpression was reduced by KC7F2. In addition, PITX1 (paired like homeodomain 1) was identified to be inhibited by ALDH1A3 knockdown, and PITX1 depletion inhibited cell proliferation. The mechanistic studies showed that ALDH1A3 knockdown reduced the acetylation of histone 3 lysine 27 (H3K27ac). Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.

Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma.

Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer histotype with generally good prognosis when diagnosed at an early stage. However, MOC with the infiltrative pattern of invasion has a worse prognosis, although to date studies have not been large enough to control for covariables. Data on reproducibility of classifying the invasion pattern are limited, as are molecular correlates for infiltrative invasion. We hypothesized that the invasion pattern would be associated with an aberrant tumour microenvironment. Four subspecialty pathologists assessed interobserver reproducibility of the pattern of invasion in 134 MOC. Immunohistochemistry on fibroblast activation protein (FAP) and THBS2 was performed on 98 cases. Association with survival was tested using Cox regression. The average interobserver agreement for the infiltrative pattern was moderate (kappa 0.60, agreement 86.3%). After reproducibility review, 24/134 MOC (18%) were determined to have the infiltrative pattern and this was associated with a higher risk of death, independent of FIGO stage, grade, and patient age in a time-dependent manner (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 3.0-34.5). High stromal expression of FAP and THBS2 was more common in infiltrative MOC (FAP: 60%, THBS2: 58%, both P < 0.001) and associated with survival (multivariate HR for FAP: 1.5 [95% CI 1.1-2.1] and THBS2: 1.91 [95% CI 1.1-3.2]). The pattern of invasion should be included in reporting for MOC due to the strong prognostic implications. We highlight the histological features that should be considered to improve reproducibility. FAP and THBS2 are associated with infiltrative invasion in MOC.

Ovarian Cancer: From Precursor Lesion Identification to Population-Based Prevention Programs.

Epithelial ovarian cancer (EOC) is a heterogeneous group of malignancies, including high-grade serous ovarian cancer (HGSC). HGSC is often diagnosed at advanced stages and is linked to TP53 variants. While BRCA variants elevate risk, most HGSC cases occur in individuals without known genetic variants, necessitating prevention strategies for people without known high-risk genetic variants. Effective prevention programs are also needed due to the lack of traditional screening options. An emerging primary prevention strategy is opportunistic salpingectomy, which involves removing fallopian tubes during another planned pelvic surgery. Opportunistic salpingectomy offers a safe and cost-effective preventative option that is gaining global adoption. With the publication of the first cohort study of patients who underwent salpingectomy, specifically for cancer prevention, attention has turned to broadening opportunities for salpingectomy in addition to more targeted approaches. Prevention opportunities are promising with increasing adoption of salpingectomy and the increased understanding of the etiology of the distinct histotypes of ovarian cancer. Yet, further research on targeted risk-reducing salpingectomy with thoughtful consideration of equity is necessary to reduce death and suffering from ovarian cancer.

Simultaneous occurrence of two distinct histotypes of ovarian endometriosis-associated cancer in bilateral ovaries: implications for monoclonal histogenesis from a case report

BackgroundTransformation of endometriosis to malignancy is a rare occurrence. Clear cell ovarian cancer and endometrioid ovarian cancer are the two histotypes most consistently linked to endometriosis. The exact pathways leading to malignant transformation of endometriosis remain elusive.Case presentationA 41-year-old woman presented to our hospital with a ten days history of abdominal pain which was not responsive to medication. Pathological examination revealed an unexpected finding of bilateral endometriosis associated with distinct malignancies: a clear cell carcinoma in the right ovary and a well-differentiated endometrioid carcinoma in the left ovary. Molecular analysis indicated a shared somatic driver mutation in ING1 in the eutopic endometrium and the bilateral ovaries while simultaneously exhibiting specific genetic alterations unique to each carcinoma. Notably, several common mutation sites were also identified, including previously reported common oncogenes (KRAS, PIK3CA, ARID1A). This finding prompts the hypothesis of a possible monoclonal origin of the two tumours.ConclusionThis case represents an exceedingly rare occurrence of two different histotypes of ovarian endometriosis-associated cancer manifesting simultaneously in bilateral ovaries. Based on genetic analysis, we hypothesize that these malignancies may have a monoclonal origin, providing insights into understanding the different biological mechanisms underlying carcinogenesis.

Detection of a status of microsatellite instability in tumors of patients with endometrioid adenocarcinoma of the ovaries and/or of uterine corpus

Introduction. Multiple primary malignant neoplasms of female reproductive organs are a rare pathology. However, over the past decades, there has been an upsurge of interest in the study of this phenomenon in oncology. This is particularly the case for the diagnosis of synchronous endometrioid adenocarcinoma of the ovaries and uterine corpus, which histogenetically belong to the same germ layer and have similar histological structure. Until recently, clinicians relied only on morphological examination in these cases, but with the development of molecular genetic technologies, new diagnostic possibilities have emerged.Aim. Is the detection of the status of microsatellite instability in tumors of patients with endometrioid adenocarcinoma of the ovaries and/or uterine corpus.Materials and Methods. A pilot retrospective molecular genetic study (n = 48) was conducted to determine the status of microsatellite instability (MSI) in the tumors of the ovaries and/or uterine corpus: it involved 33 patients with solitary endometrioid ovarian cancer and 15 patients with synchronous endometrioid adenocarcinoma of the ovaries and uterine corpus. Microsatellite instability status was detected using PCR method with subsequent fragment analysis performed on ABI PRISM 3500 genetic analyzer (8 capillaries, Applied Biosystems). DNA was isolated from paraffin blocks of surgical specimens using DNAsorb B extraction kit (AmpliSens, Russia), according to the manufacturer’s manual. DNA concentration was estimated fluorometrically using Qubit 2.0 (Life Technologies, USA). The obtained data were analyzed using GeneMapper program (Thermo Fisher, USA). In case of polymorphism of two and more markers high-level microsatellite instability (MSI-H) was observed.Results. The incidence of MSI-H in solitary endometrioid ovarian cancer (n = 33) was 12,1 % (4 cases), while in synchronous ovarian and uterine corpus tumors (n = 15) MSI-H incidence made up 20 % (n = 3). Herewith, there have been only cases of a combination of endometrioid histotypes of ovarian and endometrial cancer with identical status of microsatellite instability. Thus, the incidence of MSI-H in synchronous endometrioid adenocarcinoma of the ovaries and uterine corpus (20 %) is comparable to that in solitary endometrial cancer.Conclusion. Our pilot study became a significant complement to the previously published materials, as it allowed to confirm the clonal origin of tumors in patients with endometrioid adenocarcinoma of the ovaries and uterine corpus, that can affect the stratification of treatment strategy for this category of patients.

Immunohistochemical features of ovarian cancer

Ovarian cancer is the leading cause of death among women with gynecological oncological diseases. Diagnosis at the early stages of the disease allows for better chances of treatment and prognosis of ovarian cancer. It is reflected in the reduction of morbidity and mortality rates. An immunohistochemical study is used for differential diagnosis and accurate establishment of the histotype of ovarian cancer. Objective: to systematize literature data about the immunohistochemical features of ovarian cancer. In 90% of cases, ovarian cancer is epithelial-stromal, among which the main histological types are distinguished: serous (low- and high-grade), endometrioid, mucinous, and clear cell. In serous and other ovarian tumors, cytokeratins (CK) are widely used. CK 7 is present in all tumors, including mucinous tumors, expressing CK 20. Mucinous tumors also express villin and are negative for CDX-2. Endometrioid tumors react positively to vimentin, which is not observed in serous and mucinous tumors. Clear cell carcinoma expresses CK 8, 18, and EMA (epithelial membrane antigen).Conclusion. Therefore, immunohistochemical features of ovarian cancer ensure accuracy in the differential diagnosis of one or another histological type.

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]). To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.

Probing the Cytotoxic Signaling Induced by Eupenifeldin in Ovarian Cancer Models.

High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. Lack of early detection methods, limited therapeutic agents, and low 5-year survival rate reflect the urgent need to develop new therapies. Eupenifeldin, a bistropolone, originally isolated from Eupenicillium brefeldianum, is a cytotoxic fungal metabolite. In three HSGOC cell lines (OVCAR3, OVCAR5, OVCAR8), eupenifeldin was found to have an IC50 value less than 10 nM, while 10 times higher concentrations were required for cytotoxicity in nontumorigenic fallopian tube secretory epithelial cell lines (FTSEC). An in vivo hollow fiber assay showed significant cytotoxicity in OVCAR3. Eupenifeldin significantly increased Annexin V staining in OVCAR3 and -8, but not OVCAR5. Eupenifeldin activated caspases 3/7 in OVCAR3, OVCAR5, and OVCAR8; however, cleaved PARP was only detected in OVCAR3. Quantitative proteomics performed on OVCAR3 implicated ferroptosis as the most enriched cell death pathway. However, validation experiments did not support ferroptosis as part of the cytotoxic mechanism of eupenifeldin. Autophagic flux and LC3B puncta assays found that eupenifeldin displayed weak autophagic induction in OVCAR3. Inhibition of autophagy by cotreatment with bafilomycin reduced the toxicity of eupenifeldin, supporting the idea that induction of autophagy contributes to the cytotoxic mechanism of eupenifeldin.

К ВОПРОСУ О РИСКАХ МАЛИГНИЗАЦИИ ЭНДОМЕТРИОМ ЯИЧНИКА

Introduction. Endometriosis is a widespread gynecological disease. In the last few years, new data have been accumulating confirming that endometriosis leads to an increased risk of malignant neoplasms of the ovaries, endometrium, breast and thyroid gland. The most commonly found form of endometriosis is endometrioma. Objective: to analyze epidemiological and genetic studies of the risks of neoplastic transformation of ovarian endometriomas based on search results in electronic resources MEDLINE, EMBASE, Elibrary from 2012 to 2023. Results. Epidemiological and genetic studies have proven the risk of malignancy of endometriosis with the development of ovarian cancer related to endometriosis. Studies confirmed, that two histotypes of epithelial ovarian cancer, such as clear-cell and endometrioid cancer, most closely related to endometriosis. Genome-wide association studies (GWAS) have confirmed the risk of endometrial cancer in women with endometriosis, which was shown earlier than epidemiological studies. Finding the genes and pathways underlying these complex diseases is an essential step toward developing better diagnostic and therapeutic tools. Conclusion. The review presents epidemiological and genetic evidence of the risks of ovarian cancer and endometrial cancer in women with endometriosis.