Possible severe gastrointestinal toxicity following the first cycle of mirvetuximab soravtansine in a patient with high-grade serous ovarian carcinoma.

Objectives : To analyse the characteristics and expression patterns of Leptin in high-grade serous epithelial ovarian carcinoma (HGSC), and to compare them with the overall serous ovarian carcinoma population. Methods : This was a cross-sectional study. A total of 77 paraffin-embedded tissue samples were collected from patients at the Wahidin Sudirohusodo Hospital over a period of 3 years. Immunohistochemical staining was performed using a polyclonal Leptin antibody. Data were analyzed using SPSS version 22.0. Results: Among HGSC patients, the majority (64.3%) were over 50 years old, and a significant portion (39.3%) were obese. Leptin showed strong cytoplasmic expression in 69.6% of HGSC tumor cells and in 100% of LGSC tumor cells (p-value = 0.004). There was no correlation between lymphovascular space invasion and leptin expression. Interestingly, leptin expression in overall serous ovarian carcinoma patients exhibited a protective effect against metastasis (p-value = 0.047), suggesting a leptin paradox exists in this type of cancer. However, this association was no longer significant when the analysis excluded the LGSC group (p-value = 0.193). Conclusion : This study suggest that leptin expression may not be a significant prognostic factor in HGSC. The appearance of the pseudo-leptin paradox phenomenon in several previous studies was confounded by sample populations with heterogeneous tumor morphology. Keywords: high-grade serous carcinoma, leptin paradox, immunohistochemistry, leptin, obesity

To evaluate diagnostic accuracy of novel nanoparticle immunoassays across different histotypes of tubo-ovarian carcinoma (TOC) at diagnosis. This multicenter observational study consisted of consecutive patients (n=1,312) having surgery due to suspected ovarian pathology. Serum were analyzed with Sialyl-Thomsen-nouveau (STn) antibody and Macrophage-Galactose-Lectin (MGL) for the detection of cancer antigen 125 (CA125) and 15-3 (CA15-3) glycoforms using CA125 enzyme immunoassay (EIA), CA15-3EIA and HE4EIA as references. Receiver operating characteristics (ROC) were applied and sensitivity at 75% and 98% specificity were calculated across histotypes. TOC was present in 596 patients and 716 had benign disease. CA125STn showed higher sensitivity at 98% specificity compared with CA125EIA for high grade serous ovarian carcinoma (HGSC) (0.85 vs 0.62, p<0.001), HGSC early-stage (0.66 vs 0.24, p=0.003), and HGSC late-stage (0.90 vs 0.69, p<0.001). CA15-3STn showed higher sensitivity at 98% specificity compared to CA125EIA for mucinous ovarian carcinoma (0.50 vs 0.16, p=0.038). No improvements were found for low grade serous carcinoma (LGSC), endometrioid and clear cell histotypes. The best performing combined biomarker test was CA125STn+HE4EIA with higher sensitivity at 98% specificity for HGSC (0.93 vs 0.86, p<0.001) and HGSC late-stage (0.97 vs 0.91p<0.001) compared with CA125EIA+HE4EIA. The STn glycovariants of CA125 and CA15-3 have improved sensitivity at high specificity for high grade serous and mucinous ovarian carcinoma and often perform better than the commonly used biomarker CA125EIA.

BackgroundMicroRNAs (miRNA) are 20∼25 nucleotide non-coding RNAs that inhibit the translation of targeted mRNA, and they have been implicated in the development of human malignancies. High grade serous ovarian carcinomas, the most common and lethal subtype of ovarian cancer, can occur sporadically or in the setting of BRCA1/2 syndromes. Little is known regarding the miRNA expression profiles of high grade serous carcinoma in relation to BRCA1/2 status, and compared to normal tubal epithelium, the putative tissue of origin for high grade serous carcinomas.Methodology/Principal FindingsGlobal miRNA expression profiling was performed on a series of 33 high grade serous carcinomas, characterized with respect to BRCA1/2 status (mutation, epigenetic silencing with loss of expression or normal), and with clinical follow-up, together with 2 low grade serous carcinomas, 2 serous borderline tumors, and 3 normal fallopian tube samples, using miRNA microarrays (328 human miRNA). Unsupervised hierarchical clustering based on miRNA expression profiles showed no clear separation between the groups of carcinomas with different BRCA1/2 status. There were relatively few miRNAs that were differentially expressed between the genotypic subgroups. Comparison of 33 high grade serous carcinomas to 3 normal fallopian tube samples identified several dysregulated miRNAs (false discovery rate <5%), including miR-422b and miR-34c. Quantitative RT-PCR analysis performed on selected miRNAs confirmed the pattern of differential expression shown by microarray analysis. Prognostically, lower level miR-422b and miR-34c in high grade serous carcinomas were both associated with decreased disease-specific survival by Kaplan-Meier analysis (p<0.05).Conclusions/SignificanceHigh grade serous ovarian carcinomas with and without BRCA1/2 abnormalities demonstrate very similar miRNA expression profiles. High grade serous carcinomas as a group exhibit significant miRNA dysregulation in comparison to tubal epithelium and the levels of miR-34c and miR-422b appear to be prognostically important.

Low-grade chronic inflammation and persistent oxidative stress are hallmarks of malignant transformation. High-grade serous ovarian carcinoma (HGSOC) is a fatal malignancy of women, and the median age of its incidence is 60-65 years. Our earlier studies showed enhanced expression of interleukin 16 (IL-16, an inflammatory cytokine), its receptor CD9, and glucose-regulated protein (GRP78, a marker of cellular stress and inhibitor of DNA damage repair mechanism) in postmenopausal ovaries and patients with HGSOC as compared with premenopausal subjects. It is possible that these age-associated increases in IL-16, CD9, and GRP78 expression may contribute to HGSOC-related epigenetic modifications of gH2A histone family member X (gH2AX, a marker for double-stranded DNA breaks), and histone deacetylase 1 (HDAC1), involved in DNA repair. The goal of this study was to examine if age-associated such changes lead to HGSOC-associated malignant transformation and if so, to determine mechanisms involved in such transformation. Materials and Methods: Exploratory study: Archived tissue specimens were selected for immunohistochemical, immunoblotting, genomic studies, and immunoassays based on the review of their hematoxylin and eosin staining and final pathological reports. Specimens were grouped as normal premenopausal women (30-50 years old), normal postmenopausal women (55-85 years old), and ovarian high-grade serous carcinoma (HGSC). In vitro study: human ovarian surface epithelium (HOSE) cells were treated with or without recombinant human IL-16 (rhIL-16) and recombinant human GRP78 (rhGRP78), and small interfering RNA-GRP78 (siGRP78) for 24 hours or 48 hours. Nuclear fractionations from treated- or untreated HOSE cells or OVCAR3 (HGSOC cell line) cells were extracted. Results: Compared to premenopausal women, a subset of postmenopausal women exhibited significantly elevated expression (P&amp;lt;0.01) of inflammatory markers IL-16, and its receptor CD9, as well as a marker of oxidative stress (GRP78). Additionally, markers of epigenetic changes, including gH2AX and HDAC1, presented similar patterns of increase in their expression. These observations were also consistent in HGSOC patients. Enhanced expression of GRP78, gH2AX, HDAC1, and CD9 in rhIL-16 treated HOSE cells like OVCAR3 cells and their reduction in siGRP78 treated HOSE cells suggests that age-associated increase in IL-16 in postmenopausal women may be a risk factor for malignant transformation and GRP78 may be a mechanism for IL-16-induced HGSOC development. Thus, IL-16 and GRP78 represent novel targets that may be used to develop novel targeted therapies to prevent HGSOC. Expression of gH2AX and HDAC1 increased in rhGRP78-treated HOSE cells. Conclusion: The results of this study suggest that age-associated increases in IL-16 (a marker of chronic inflammation) and GRP78 (a marker of oxidative stress) may contribute to the predisposition for HGSOC-associated malignant transformation. IL-16 and GRP78 offer potential targets for the prevention of HGSOC in women. Support: The Portes Foundation Citation Format: Jessica Ramirez, Animesh Barua. Interleukin-16 is a novel target to prevent age-associated epigenetic changes leading to malignant transformation associated with ovarian high-grade serous carcinoma (HGSOC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A054.

The two most prevalent subtypes of epithelial ovarian carcinoma (EOC) are ovarian clear cell carcinoma (OCCC) and high-grade serous ovarian carcinoma (HGSC). Patients with OCCC have a poor prognosis than those with HGSC due to chemoresistance, implying the need for novel treatment target. In this study, we applied single-cell RNA sequencing (scRNA-seq) together with bulk RNA-seq data from the GEO (Gene Expression Omnibus) database (the GSE189553 dataset) to characterize and compare tumor heterogeneity and cell-level evolution between OCCC and HGSC samples. To begin, we found that the smaller proportion of an epithelial OCCC cell subset in the G2/M phase might explain OCCC chemoresistance. Second, we identified a possible pathogenic OCCC epithelial cell subcluster that overexpresses LEFTY1. Third, novel biomarkers separating OCCC from HGSC were discovered and subsequently validated on a wide scale using immunohistochemistry. Amine oxidase copper containing 1 (AOC1) was preferentially expressed in OCCC over HGSC, while S100 calcium-binding protein A2 (S100A2) was detected less frequently in OCCC than in HGSC. In addition, we discovered that metabolic pathways were enriched in the epithelial compartment of the OCCC samples. In vitro experiments verified that inhibition of oxidative phosphorylation or glycolysis pathways exerted direct antitumor effects on both OCCC and HGSC cells, while targeting glutamine metabolism or ferroptosis greatly attenuated chemosensitivity only in OCCC cells. Finally, to determine whether there were any variations in immune cell subsets between OCCC and HGSC, data from scRNA-seq and mass cytometry were pooled for analysis. In summary, our work provides the first holistic insights into the cellular and molecular distinctions between OCCC and HGSC and is a valuable source for discovering new targets to leverage in clinical treatments to improve the poor prognosis of patients with OCCC.

Background: High grade serous ovarian carcinoma (HGSOC) is a highly lethal gynecologic malignancy with a typical 5-year survival rate of 40% or less when diagnosed with late-stage disease. There is currently no single effective screening tool for high risk or community-based risk assessment for HGSOC and multivariate tests for preselected patients are suboptimal. In women with a known pelvic mass, surgery followed pathological assessment is currently the only definitive way to diagnose HGSOC. About 15% of women with a suspicious mass will have HGSOC and less than 15% will present with stage 1 cancer. A liquid biopsy assay based on cell-free (cf)DNA enables non-invasive dynamic assessment of disease status in patients with cancer where cfDNA methylation is particularly promising for detection of early stage HGSOC. The goal of the current study is to develop a cfDNA methylation liquid biopsy that can be used for the screening and risk assessment for HGSOC. Methods: Tissue and plasma samples were acquired under informed consent from multiple commercial and academic sources. Reduced representation bisulfite sequencing (RRBS) was performed on 33 HGSOC tissues as well as 8 normal ovary and 13 normal fallopian tube controls. Differentially methylated regions (DMRs) were called between HGSOC and normal controls using metilene and DSS. DMR calls with p-values &amp;lt; 0.05 and |αβ| &amp;gt; 0.45 (n = 1677 DMRs) were used to generate a targeted tissue-based methylation assay using the myBaits® hybrid probe capture platform (Daicel Arbor Biosciences). Next, targeted enrichment was performed on bisulfite converted plasma cfDNA on an independent set of 84 HGSOC samples (27 stage 1, 20 stage 2, 37 stage 3) and 100 samples from patients with benign ovarian masses. Mean beta value across DMRs were used to train a novel cfDNA methylation classifier model called OvaPrintTM to discriminate HGSOC from benign masses using a repeated 3-fold cross validation approach to obtain an unbiased estimate of the performance of the classifier. The average cross validated score for each sample was used to generate a receiver operator characteristic (ROC) curve. Results. RRBS analysis on HGSOC tissue and normal tissue controls demonstrated excellent separation of HGSOC from normal tissue samples using the selected DMRs. OvaPrintTM testing in an independent cohort of 184 plasma samples discriminated HGSOC from benign tumors with a high sensitivity and specificity (area under curve (AUC) = 0.931) using cfDNA methylation. Conclusions: OvaPrintTM is a novel cfDNA methylation liquid biopsy that can be used for effective cancer risk assessment for HGSOC in women presenting with pelvic masses. Citation Format: David N. Buckley, Gerald Gooden, Lee Shulman, Monica Newman, Mona Guo, Ben Yi Tew, Lynda Roman, Juan Pablo Lewinger, Bodour Salhia. OvaPrint - a novel cfDNA methylation liquid biopsy for cancer risk assessment in high grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1025.

Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube (FT) epithelium, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HGSOC). Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HGSOC hinges on the development of novel model systems. The tubal hypothesis of serous tumorigenesis has led us to develop a number of experimental platforms. These platforms provide us with a unique view into the susceptibilities of the FT epithelium to neoplastic transformation and provide a vehicle to query the contribution of any given genetic alteration to tumor development in vitro and in vivo. These models include the ex-vivo bioanalytical platform of benign FT epithelium, the in vitro FT secretory cell transformation model, a series of patient-derived primary tumor xenograft (PDX) models that retain the phenotypic and genotypic properties of the original patient tumors, and a genetically-engineered mouse model (GEMM) that specifically targets the FT epithelium in vivo. Our GEM model specifically targets the Müllerian secretory cell. It uses the Pax8 promoter to drive expression of the Cre recombinase in the fallopian tube (FT) secretory cells. Pax8 is a lineage marker for the Müllerian system. It is necessary for the development of the female reproductive tract and its expression is retained in the adult FT secretory cell and in nearly all HGSOCs. By crossing our Pax8-Cre deletor mouse with mice carrying floxed alleles of BRCA genes, TP53 (or mutant) and/or PTEN, we could specifically manipulate the expression of these genes in the FT secretory cell. Using this approach, in collaboration with the laboratory of Daniela Dinulescu, we showed that HGSOC can originate in secretory cell of the FT and also established that serous tubal intraepithelial carcinoma (STIC) is the precursor lesion to high-grade serous ovarian and peritoneal carcinomas. Importantly, the tumors that arise in this model not only look like high-grade serous carcinomas but they also retain the genomic complexity that is a hallmark of human HGSOC. In addition to providing mechanistic insight into the origin and pathogenesis of HGSC, this model provides a platform to explore HGSOC sensitivity to novel therapeutic strategies and to develop better detection strategies for early tumor diagnosis in high-risk women. Citation Format: Ronny Drapkin. Discovering the distal fallopian tube as the origin for high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA5.

To study the morphologic changes of fallopian tubal epithelium in patients with ovarian serous epithelial tumors and to explore the relationship between the tubal epithelial changes and tumorigenesis of serous ovarian carcinoma. The fallopian tubes in 79 cases of high-grade serous ovarian carcinoma, 12 cases of low-grade serous ovarian carcinoma, 16 cases of serous borderline ovarian tumor and 11 cases of non-ovarian benign tumors were serially examined under light microscope. Immunohistochemical study with EnVision method was used to detect the expression of p53 and bcl-2 protein in the fallopian tubal epithelium in all cases. The occurrences of secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial carcinoma (STIC) and serous invasive carcinoma were analyzed. SCOUT in tubal epithelium was observed in 60.8% (48/79) of the high-grade serous carcinoma group, 4/12 of the low-grade serous carcinoma group, 3/16 of the serous borderline tumor group and 2/11 of the non-ovarian benign tumor group (P = 0.001). P53 signature, STIC and serous invasive carcinoma occurred only in the fallopian tubal epithelium of patients with high-grade serous ovarian carcinoma, with the positive rates being 29.1% (23/79), 15.2% (12/79) and 44.3% (35/79), respectively. Of the 23 cases with p53 signature, 17 cases had solitary lesion and 6 cases involved more than two sites. A total of 33 p53 signature positive foci were found, with 22 foci located at fimbria and 11 at ampulla. Bcl-2 expression was demonstrated in 90.9% of those foci (30/33). Of the 12 patients with STIC, 7 cases were solitary and 5 cases involved more than two sites. A total of 18 STIC foci were found, with 16 foci located at fimbria and 2 at ampulla. All of them were positive for bcl-2. SCOUT is found in fallopian tubal epithelium in patients with serous ovarian epithelial tumors, especially high-grade serious carcinoma. On the other hand, p53 signature, STIC and invasive serous carcinoma of tubal epithelium are observed only in patients with high-grade serous ovarian carcinoma, with a predilection of fimbrial involvement. Correlation exists between SCOUT, p53 signature, STIC and high-grade serous ovarian carcinomas. Bcl-2 and p53 immunostaining is helpful for demonstrating such lesions.

Background: High-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer. It has a high mortality rate, even after successful first-line treatment with debulking surgery and chemotherapy. Although therapeutic options for targeted therapy are rapidly expanding, identification of patients who respond to these therapies remains a challenge. In recognition of the importance of the functional phenotype of cancer cells, Verhaegh et al. (Cancer Res 2014) developed assays to measure functional activity of signal transduction pathways (STPs) based on mRNA expression levels of pathway-specific target genes. In this study, we aimed to identify HGSCs with STP activity with a potential clinical target by comparing their activity with STP activity in normal Fallopian tube epithelium (FTE), the tissue of origin of most HGSCs. Methods: We included 50 primary tumor samples taken prior to start of chemotherapy of postmenopausal patients diagnosed with advanced stage HGSC and 9 morphologically normal FTE samples of healthy postmenopausal women. Using pathway assays, we assessed functional pathway activity of the androgen receptor (AR), estrogen receptor (ER), PI3K, MAPK, Hedgehog, TGFβ and Notch pathways. Differences in STP activity between groups were compared with Mann-Whitney U tests. Cut-off value for aberrant STP activity was defined as two standard deviations above the mean value of STP activity measured in FTE samples. Results: In the HGSC group we observed lower median ER (p &amp;lt; 0.001) pathway activity and higher median PI3K (p &amp;lt; 0.001), Hedgehog (p &amp;lt; 0.001) and TGFβ pathway (p = 0.020) activity as compared to the FTE group. In individual HGSC samples, aberrant activity was identified for the MAPK (n = 10), PI3K (n = 22), Hedgehog (n = 28) and TGFβ (n = 21) pathways. Frequently observed combinations of aberrant STP activity were Hedgehog/TGFβ (n = 12) and Hedgehog/PI3K (n = 9). In total, we identified at least one STP with potential clinical target in 88% (44/50) of HGSC samples. Conclusions: Our analysis enabled the identification of STP activity with a potential clinical target in 88% of the analyzed HGSC samples. Differentiation between normal and aberrant STP activity could have clinical utility in the selection of HGSC patients for targeted therapy. A prospective study (STAPOVER) has been designed to demonstrate clinical utility. Citation Format: Phyllis Van der Ploeg, Yvonne J.W. Wesseling-Rozendaal, Eveline C. Biezen-Timmermans, Jurgen M.J. Piek. Identification of signal transduction pathway activity with potential clinical target in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4002.

Impact of neoadjuvant chemotherapy duration on the survival of patients with advanced stage high-grade serous or endometrioid ovarian carcinoma (359)

Backgroud: Ovarian carcinoma is the third most common malignancy in Indonesian women after breast and cervical cancer. Serous ovarian carcinoma is the most frequent subtype, divided into low-grade and high-grade types, each with distinct genetic and biological characteristics. Objective:This study aims to compare the clinicopathological features of high-grade and low-grade serous ovarian carcinoma. Methods: A retrospective cross-sectional study was conducted using 77 paraffin-embedded samples of serous ovarian carcinoma. Clinical and pathological data including age, body mass index (BMI), age at menarche, and parity were collected and analyzed using the chi-square test. Results: Patients aged &gt;50 years accounted for most cases, with 64.3% presenting high-grade serous carcinoma (HGSC). Overweight/obesity was observed in 40.3% of cases. Early menarche (&lt;13 years) was reported in 78%, and 42.7% were multiparous. No significant differences were found in clinical variables between HGSC and low-grade serous carcinoma (LGSC). Histopathologically, HGSC showed more pronounced cytologic atypia, necrosis, and metastasis. Conclusion: High-grade serous carcinoma demonstrates greater aggressiveness compared to its low-grade counterpart. Histopathological assessment plays a critical role in diagnosis, treatment decisions, and prognosis evaluation.

Neuroendocrine differentiation in high-grade serous ovarian carcinomas has only rarely been described. However, in our consultancy experience, we have been pointed at a case of neuroendocrine relapse in a patient with high-grade serous ovarian carcinoma where retrospectively, a minor neuroendocrine component in the primary tumor could be detected. Hypothesizing that immunohistochemical evidence of neuroendocrine differentiation might be more frequent in ovarian carcinoma than suspected by morphology, we immunophenotyped the tissue microarrays (TMAs) of a cohort of 178 high-grade serous carcinomas for chromogranin and synaptophysin expression. Synaptophysin expression was found in 12 (6.7 %) out of 172 patients, and chromogranin A expression was seen in 36 (20.7 %) out of 174 patients. Kaplan-Meier analysis revealed that carcinomas with synaptophysin expression of >20 % of positive cells (n = 4) had a significantly shorter survival time than those with 0-20 % of positive cells (p < 0.0001). Synaptophysin expression remained a significant prognostic factor in multivariate analysis (HR = 10.82, 95 % confidence interval 3.10-37.71, p < 0.0001), independently of age, FIGO stage, and residual tumor after surgery. A trend toward shorter survival was seen in patients with tumors that expressed chromogranin, irrespective of the amount of positive cells (p = 0.173). A neuroendocrine differentiation is important to keep in mind when a neuroendocrine tumor of unknown primary is detected in regional or temporal connection with an ovarian carcinoma. A minor neuroendocrine component in ovarian high-grade serous carcinomas might imply a dismal prognosis.

DNA damage commonly occurs in cancer cells as a result of endogenous and tumor microenvironmental stress. In this study, we applied immunohistochemistry to study the expression of phosphorylated Chk2 (pChk2), a surrogate marker of the DNA damage response, in high grade and low grade of ovarian serous carcinoma. A phospho-specific antibody specific for threonine 68 of Chk2 was used for immunohistochemistry on a total of 292 ovarian carcinoma tissues including 250 high-grade and 42 low-grade serous carcinomas. Immunostaining intensity was correlated with clinicopathological features. We found that there was a significant correlation between pChk2 immunostaining intensity and percentage of pChk2 positive cells in tumors and demonstrated that high-grade serous carcinomas expressed an elevated level of pChk2 as compared to low-grade serous carcinomas. Normal ovarian, fallopian tube, ovarian cyst, and serous borderline tumors did not show detectable pChk2 immunoreactivity. There was no significant difference in pChk2 immunoreactivity between primary and recurrent high-grade serous carcinomas. In high-grade serous carcinomas, a significant correlation (P < 0.0001) in expression level (both in intensity and percentage) was found between pChk2 and Rsf-1 (HBXAP), a gene involved in chromatin remodeling that is amplified in high-grade serous carcinoma. Our results suggest that the DNA damage response is common in high-grade ovarian serous carcinomas, especially those with Rsf-1 overexpression, suggesting that Rsf-1 may be associated with DNA damage response in high-grade serous carcinomas.

Introduction: The most common malignancy of the ovary is serous carcinoma, which can be classified as either Low-grade Serous Ovarian Carcinoma (LGSOC) or High-grade Serous Ovarian Carcinoma (HGSOC) and originates from the surface epithelium. However, the overall prognosis for both cancers is very poor. Immunohistochemical analysis of p53 and p16 expression is commonly used to detect mutations. Diffuse and strong mutations (mutant type) are almost always observed in cases of HGSOC, while focal expression (wild type) suggests the absence of mutations in HGSOC. LGSOCs are characterised by a low number or absence of genetic mutations. Aim: To investigate the association between p53 and p16 expression in different grades and stages of Serous Ovarian Carcinoma (SOC). Materials and Methods: This observational cross-sectional descriptive study was conducted on 62 patients diagnosed with ovarian serous carcinoma. The study focused on examining the expressions of p53 and p16 using Immunohistochemistry (IHC) in the Department of Pathology, Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal, India, over a period of one and a half years (February 2021 to July 2022). The study parameters included clinical features, histological findings, staging, The Federation of Gynaecology and Obstetrics (FIGO), grading, p53 and p16 expression by IHC in all cases, and the association between p53 and p16 expression with the grade and stage of the cancer. Statistical analysis was performed using Analysis of Variance (ANOVA) and Statistical Package for Social Sciences (SPSS) software. A p-value of less than 0.05 was considered significant. Results: A total of 62 cases were included in the study, with 55 cases (88.70%) classified as LGSOC and 7 cases (11.29%) as HGSOC. The mean age for LGSOC was 53.5 years, while for HGSOC it was 54 years. Among the HGSOC cases (n=55), 45 cases (81.80%) showed diffuse positive results (mutant type) for p53. In contrast, there was no diffuse p53 expression in LGSOC cases (n=7), with 5 cases (71.40%) showing focal positivity (wild type). The p-value for comparing p53 expression in both cases was significant (&lt;0.00001). As for p16 expression, among the HGSOC cases (n=55), 31 cases (56.40%) showed diffuse positivity (mutant type), while among the LGSOC cases (n=7), most of the cases, 5 cases (71.40%), showed focal positivity (wild type). The p-value for comparing p16 expression in both cases was significant (&lt;0.003794). Conclusion: In conclusion, p53 along with p16 are good markers for grading SOC, and p53 is highly effective in differentiating HGSOC from LGSOC based on the positivity pattern (diffuse and strong positive for high-grade/mutant type, and focal positive for low-grade cancers). Thus, p53 has become an attractive target for the development of moleculetargeted therapies for this disease.

Ovarian clear cell carcinoma (OCCC) is a special histological type of epithelial ovarian cancer (EOC) that is not derived from epithelial cells of the ovarian or fallopian tube as the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), but is closely related to endometriosis and similar to endometrial clear cell carcinoma (ECCC) at morphologic and phenotypic features. However, limited data was shown in OCCC genomic features and compared with that in OCCC, HGSOC and ECCC. Herein, we utilized next-generation sequencing analysis of a panel of 1,021 genes to profile the mutational alterations in 34 OCCC and compared them to those from HGSOC (402 cases) and ECCC (30 cases). In result, the ARID1A and PIK3CA are high-frequency mutations of OCCC. Clonal architectures showed that all the mutations of genes occur in the later stage in the OCCC progress, whereas KRAS mutation is the earlier event compared with mutation of ARID1A or PIK3CA, which usually occurs in a group of ARID1A or PIK3CA mutations. The mutation frequency of main driver genes is similar between OCCC and ECCC, while TP53 is the main mutation in HGSOC and ECCC. Shared mutational signatures between OCCC and ECCC tissues with commonly observed a C>T change indicated a common carcinogens-exposed between these two carcinomas, but HGSOC and ECCC have common and distinct mutational signatures across cohorts respectively. In addition, we identified some novel CNV gains in NF1, ASXL1, TCF7L2, CREBBP and LRP1B and loss in ATM, FANCM, RB1 and FLT in OCCC. Our study offered a new perspective for OCCC tumorigenesis from two organs, the ovary and uterus, at genomic architectures and revealed novel CNV events for helping to provide theoretical support for OCCC treatment.