Ovarian Endometrioid Carcinoma Research Articles

Next-generation genomic sequencing is a useful tool for differentiating between ovarian endometrioid carcinoma and endometrial endometrioid carcinoma (183)

Objectives: To determine the difference in molecular signatures specific to ovarian endometrioid carcinoma and endometrial endometrioid carcinoma using next-generation cancer genomic sequencing data. Methods: Next-generation sequencing data for ovarian endometrioid carcinoma and endometrial endometrioid carcinoma were obtained from the American Association for Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (Project GENIE). All specimens were assessed for the occurrence of any molecular alteration within the most frequently mutated genes in both tumor types. Multivariable logistic regression was then used to determine molecular predictive models specific to ovarian endometrioid carcinoma versus endometrial endometrioid carcinoma. Results: The top 105 mutated genes in both tumor types were queried in 1,813 total tumor specimens, including 181 ovarian endometrioid carcinoma and 1,632 endometrial endometrioid carcinoma. Mutations in the following genes were positively associated with the ovarian endometrioid carcinoma histology (odds ratio, 95% CI, p-value): CTNNB1 (1.728, 1.226-2.435, 0.002), MGA (3.248, 1.653-6.379, <0.001), KDM6B (4.082, 1.385-12.027, 0.011), CIITA (2.758, 1.210-6.288, 0.016), and ENG (6.637, 1.591-27.695, 0.009). Mutations in the following genes were positively associated with the endometrial endometrioid carcinoma histology (odds ratio, 95% CI, p-value): PIK3CA (1.469, 1.037-2.082, 0.030), PTEN (2.997, 2.079-4.319, <0.001), PIK3R1 (1.935, 1.176-3.186, 0.009), CTCF (2.105, 1.091-4.065, 0.027), ZFHX3 (2.890, 1.123-7.440, 0.028), and BCOR (3.753, 1.809-7.786, <0.001). Objectives: To determine the difference in molecular signatures specific to ovarian endometrioid carcinoma and endometrial endometrioid carcinoma using next-generation cancer genomic sequencing data. Methods: Next-generation sequencing data for ovarian endometrioid carcinoma and endometrial endometrioid carcinoma were obtained from the American Association for Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (Project GENIE). All specimens were assessed for the occurrence of any molecular alteration within the most frequently mutated genes in both tumor types. Multivariable logistic regression was then used to determine molecular predictive models specific to ovarian endometrioid carcinoma versus endometrial endometrioid carcinoma. Results: The top 105 mutated genes in both tumor types were queried in 1,813 total tumor specimens, including 181 ovarian endometrioid carcinoma and 1,632 endometrial endometrioid carcinoma. Mutations in the following genes were positively associated with the ovarian endometrioid carcinoma histology (odds ratio, 95% CI, p-value): CTNNB1 (1.728, 1.226-2.435, 0.002), MGA (3.248, 1.653-6.379, <0.001), KDM6B (4.082, 1.385-12.027, 0.011), CIITA (2.758, 1.210-6.288, 0.016), and ENG (6.637, 1.591-27.695, 0.009). Mutations in the following genes were positively associated with the endometrial endometrioid carcinoma histology (odds ratio, 95% CI, p-value): PIK3CA (1.469, 1.037-2.082, 0.030), PTEN (2.997, 2.079-4.319, <0.001), PIK3R1 (1.935, 1.176-3.186, 0.009), CTCF (2.105, 1.091-4.065, 0.027), ZFHX3 (2.890, 1.123-7.440, 0.028), and BCOR (3.753, 1.809-7.786, <0.001).

Feasibility of international trials of rare epithelial ovarian cancers based on trends in the United States and Asia (163)

Objectives: To investigate the feasibility of international clinical trials in rare ovarian cancers by first studying the incidence and trends of the rare histologic subtypes in the United States (US) and Asia. Methods: Data were obtained from the United States Cancer Statistics (USCS) Public Use Databases and Taiwan Cancer Registry of Taiwan Health and Welfare Data Center (HWDC) for a diagnosis of ovarian clear cell carcinoma, endometrioid carcinoma, mucinous carcinoma, or carcinosarcoma between 2001 to 2017. SEER*Stat 8.3.9, Joinpoint regression program 4.8.0.1, and Excel were used to calculate the incidence and trends. Results: In 2017, the incidence of ovarian clear cell carcinoma, endometrioid carcinoma, mucinous carcinoma, or carcinosarcoma was 0.81, 0.51, 0.47, or 0.25 per 100,000 in the US, and 1.58, 1.17, 1.08, or 0.15 per 100,000 in Asia, respectively. Over the last 18 years, the average annual percent change (AAPC) in clear cell carcinoma did not change in the US and increased by 6.2% in Asia. The AAPC for ovarian endometrioid carcinoma decreased by 2.7% in the US and increased by 2.9% in Asia. Although the rate of carcinosarcoma is increasing in both the US and Asia, it is 16-fold higher in Asia compared with the US, with an AAPC for ovarian carcinosarcoma of 6.4% in Asia versus 0.4% in the US. The rate of ovarian mucinous carcinoma decreased in both the US and Asia with an AAPC of 2.0% versus 0.9%, respectively. Conclusions: The AAPC of ovarian clear cell carcinoma, endometrioid carcinoma, and carcinosarcoma is increasing at higher rates in Asia than in the US, providing justification to utilize global recruitment strategies for clinical trial investigational treatments and interventions in rare ovarian cancers. Objectives: To investigate the feasibility of international clinical trials in rare ovarian cancers by first studying the incidence and trends of the rare histologic subtypes in the United States (US) and Asia. Methods: Data were obtained from the United States Cancer Statistics (USCS) Public Use Databases and Taiwan Cancer Registry of Taiwan Health and Welfare Data Center (HWDC) for a diagnosis of ovarian clear cell carcinoma, endometrioid carcinoma, mucinous carcinoma, or carcinosarcoma between 2001 to 2017. SEER*Stat 8.3.9, Joinpoint regression program 4.8.0.1, and Excel were used to calculate the incidence and trends. Results: In 2017, the incidence of ovarian clear cell carcinoma, endometrioid carcinoma, mucinous carcinoma, or carcinosarcoma was 0.81, 0.51, 0.47, or 0.25 per 100,000 in the US, and 1.58, 1.17, 1.08, or 0.15 per 100,000 in Asia, respectively. Over the last 18 years, the average annual percent change (AAPC) in clear cell carcinoma did not change in the US and increased by 6.2% in Asia. The AAPC for ovarian endometrioid carcinoma decreased by 2.7% in the US and increased by 2.9% in Asia. Although the rate of carcinosarcoma is increasing in both the US and Asia, it is 16-fold higher in Asia compared with the US, with an AAPC for ovarian carcinosarcoma of 6.4% in Asia versus 0.4% in the US. The rate of ovarian mucinous carcinoma decreased in both the US and Asia with an AAPC of 2.0% versus 0.9%, respectively. Conclusions: The AAPC of ovarian clear cell carcinoma, endometrioid carcinoma, and carcinosarcoma is increasing at higher rates in Asia than in the US, providing justification to utilize global recruitment strategies for clinical trial investigational treatments and interventions in rare ovarian cancers.

Patterns of spread and genetic mutations of primary endometrioid carcinomas of the ovary (168)

<b>Objectives:</b> Primary endometrioid carcinoma of the ovary is rare and comprises approximately ten percent of all primary ovarian carcinomas. Less is known about their pattern of spread and genetic alterations. Thus, the objective of this study was to characterize patterns of spread, rate of recurrence, and genetic mutations in a cohort of patients with primary endometrioid ovarian carcinoma. <b>Methods:</b> After obtaining institutional review board approval, all patients diagnosed with primary endometrioid adenocarcinoma of the ovary between January 1, 2012, and May 11, 2021, we re identified from an institutional pathology database. All tissue diagnoses were subject to expert pathologic review to confirm accuracy. Patients with co-existing neoplasms were excluded. Demographic and disease-related data were collected from pathology reports and clinical records, and time to recurrence and death were calculated if applicable. Statistical analyses were performed using SAS statistical software version 9.4. <b>Results:</b> Sixty-three patients were identified for analysis. Median age at diagnosis was 60 years (range: 22-90) and the median CA-125 at presentation was 133 U/mL (mean: 1140 U/mL, range: 7-21,545 U/mL). Assigned FIGO stage after surgery included IA in 17 (27%), IC in 24 (38%), II in 17 (27%), III in four patients (6%), and assigned histologic grades were: grade 1 in 32%, grade 2 in 43%, and grade 3 in 25% of patients. The mean ovarian tumor size was 12.7cm (range: 4.1-22cm). At either primary or re-staging surgery, 41 (65%) patients had pelvic lymph node sampling, and 33 (52%) had para-aortic lymph node sampling. The median number of pelvic lymph nodes removed was 12 (mean: 13.1; range: 1-46), and the median number of paraaortic lymph nodes removed was six (mean: 8.7; range: 1-46). All assessed lymph nodes were negative for metastases. Twenty-eight patients had germline mutational status documented. Only two patients had pathologic mutations identified - one in <i>BRCA1</i> and one in <i>BRCA2</i>. One additional patient was found to have two variants of unknown significance (VUS) in the <i>BRCA2</i> gene. Two further patients were negative for germline <i>BRCA</i> mutations but had a positive HRD score on tumor analysis. Median follow-up for patients alive at the time of data cutoff was 42 months (range: 4-70). The median progression-free survival (PFS) and overall survival (OS) for the cohort of patients who completed primary therapy were 42 and 44 months, respectively. Ten out of 63 patients (16%) experienced recurrence(s) with a median time to recurrence of 25 months. Four patients died of disease with a median OS of 31 months. <b>Conclusions:</b> No nodal metastases were identified in a cohort of comprehensively surgically staged patients with primary endometrioid ovarian carcinoma. Surgeons may consider omitting re-staging operations in patients with partially-staged but completely resected endometrioid carcinoma, regardless of grade. Germline <i>BRCA1</i> and <i>BRCA2</i> mutations were seen less frequently compared to high-grade serous carcinomas.

Retinol dehydrogenase 10 contributes to cancer stemness and intracellular carbohydrate storage in ovarian clear cell carcinomas.

Ovarian clear cell carcinomas (OCCCs) have been recurrent and refractory among the present treatments, so novel therapeutics are urgently needed. The present study accumulates the proof of concept to examine the feasibility of RDH10 as a therapeutic target for treating OCCCs. Immunohistochemically, RDH10 expression was evaluated in 111 primary epithelial ovarian cancers, including 55 OCCCs, 31 ovarian endometrioid carcinomas and 25 ovarian serous carcinomas. The spherogenecity provoked by RDH10 was evaluated in OCCC cells. To analyze whether RDH10 promotes carbohydrate storage via the vitamin A-gluconeogenesis pathway, phosphoenolpyruvate carboxykinase 1 (PCK1) protein levels and intracellular carbohydrate content were measured in response to modified RDH10 expression. Abundant RDH10 was expressed specifically in OCCCs. RDH10 promoted spherogenecity and intracellular carbohydrate storage via modulation of PCK1 expression in OCCC cells. In the present study, abundant RDH10 contributed to cancer cell stemness and intracellular carbohydrate storage in OCCCs. RDH10 is a potentially, new therapeutic candidate for treating OCCC cases.

Definitive study shows no association between ARID1A mutation status and clinical outcome in endometriosis-related ovarian cancers‡.

The ARID1A tumour suppressor protein is a component of the SWI/SNF chromatin remodelling complex, which is mutated in approximately 20% of all human cancers. ARID1A mutational status is considered to hold prognostic significance in a range of solid malignancies, yet in endometriosis‐related ovarian carcinomas there has been a lack of clarity of its prognostic role. Moreover, the relationship between ARID1A status and immune infiltrate is also poorly understood. In a recent issue of The Journal of Pathology, a large comprehensive study by Heinze, Nazeran et al addressed these areas by reviewing 1,623 endometriosis‐associated ovarian carcinomas and correlating ARID1A status using standardised immunohistochemistry to infer mutation status, with comprehensive clinicopathological features, mismatch repair status and CD8+ tumour infiltrating lymphocytes. The study definitively showed that ARID1A status does not provide any independent prognostic value in endometriosis‐associated ovarian carcinomas. ARID1A loss was, however, shown to be associated with mismatch repair deficiency and increased CD8+ tumour infiltrating lymphocytes in endometrioid ovarian carcinoma, which may be relevant for future studies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

O-094 Pathological/theoretical viewpoint

Abstract Endometriosis is a benign gynaecological disease. As the lifetime risk of developing an adenocarcinoma of the endometrium is about 2% in the general female population, there seems to be no reason to believe that the same type of mucosa should not undergo malignant derailments at a similar rate when displaced at ectopic sites. The endometrioid ovarian carcinomas and the clear cell ovarian carcinomas are the most frequent histotypes associated with endometriosis. However, determining whether the mere presence of endometrium at ectopic sites should be considered per se a premalignant condition seems crucial and constitutes the conceptual base of any strategy aimed at preventing and treating endometriosis-associated ovarian cancer. Lesions are defined “precancerous” based on definite epidemiologic, morphologic, molecular, and biologic criteria that imply the acquisition of genetic, karyotypic, structural, or functional changes in a cluster of cells that differentiate them from the surrounding normal tissue. In other words, premalignant lesions should reflect an intermediate stage along the pathway leading to cancer. The transformation of a normal cell into a cancer cell is due to the progressive acquisition of driver mutations. With the improvement of sequencing technology, several studies focusing on genomic features or molecular targets have been performed in endometriosis. In particular, studies have evaluated somatic cancer-associated mutations in endometriotic lesions without concurrent cancer to assess whether endometriosis might be considered as a precursor of cancer. It has been reported recently that several ovarian and deep endometriosis lesions harbour cancer-associated mutations. Cancer-driver mutations involve genes coding for AT-rich interactive domain-containing protein 1A (ARID1A), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA), Kirsten rat sarcoma (KRAS), or protein phosphatase 2 scaffold subunit Aα (PPP2R1A). These mutations are quite frequent also in deep endometriosis and this result is surprising considering that deep infiltrating endometriotic lesions very rarely undergo malignant transformation. This poses some doubts on the real oncogenic potential of these mutations. On the other hand, a specific role seems to be played by the ovarian microenvironment in increasing the risk of malignant derailment. The chronic inflammatory environment of women with endometriosis may theoretically facilitate the transformation of abnormal endometrial cell into a malignant cell. The micro-environmental factors such as oxidative stress, immune cell dysfunction, steroid hormones, and stem cells required for malignant transformation have been found in endometriosis. Driver gene mutations have been identified at the genetic level also in the normal endometrium, which is the origin of endometriosis. The next issue is to clarify a trigger of carcinogenesis based on genomic lineage from normal endometrium to ovarian cancers via endometriosis. To address these issues, multiomics analysis combining genomics, transcriptomics, and proteomics will be necessary.

Clinical implications of tumor-based next-generation sequencing in ovarian cancer.

5545 Background: Epithelial ovarian cancer is genetically heterogeneous, both among and within histologic subtypes. Advances in next-generation sequencing have made it feasible to ascertain the somatic genetic signature of each patient, however, critical analysis of population-level sequencing results is required to maximize the potential of this technology. Here, we aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in a large cohort of patients with high-grade epithelial ovarian cancer. Methods: Our study population comprised patients with high-grade serous (n = 972), clear cell (n = 33), endometrioid (n = 28), mucinous (n = 4), and mixed (n = 34) or unspecified (n = 21) epithelial ovarian carcinoma diagnosed between April 2013 and September 2021. tbNGS results were identified within the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected for patients who had undergone tbNGS. Progression-free survival (PFS) and overall survival (OS) were calculated from date of first treatment to date of first recurrence and date of death, respectively. Data were analyzed using descriptive statistics, univariate and multivariate Cox regression models, and clustering analyses. Results: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results identified. Nearly all (96.1%) revealed one or more genetic aberrations. Most patients (74.6%) had an actionable mutation, defined as relaying eligibility for a targeted treatment or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations; and CCNE1 amplification. Ten different targeted institutional and commercial panels were employed, covering a range of 35 to 600+ gene loci. The median time from diagnosis to testing was 14.5 months, likely corresponding to time of recurrence. Though no standalone alterations were significantly related to survival, multivariate and clustering analyses identified several genetic patterns which corresponded to patient outcomes. Mutation of BRAF, PIK3R1, NOTCH3, MET, and/or ATR was correlated with shorter PFS (HR 1.84, p = 0.001); mutation of ATM, RB1, CDKN2A, FGFR1, and/or FGFR2 was associated with improved PFS (HR 0.64, p = 0.04), as was mutation of NBN and/or ATRX (HR 0.54, p &lt; 0.05). MYC, NOTCH3, and/or CREBBP mutations were significantly correlated with worse OS (HR 1.95, p = 0.02). In our population, 40 patients (9.78%) were enrolled in genotypically-relevant clinical trials. Conclusions: tbNGS is prevalent at our institution, and often yields actionable information. We identified several mutational patterns that correlate to patient survival. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools.

Clinical analysis of 23 cases with simultaneous double primary gynecological malignant tumors

Objective: To investigate the clinicopathological features, diagnosis, treatment and prognosis of simultaneous double primary gynecological malignant tumors. Methods: A total of 23 patients with simultaneous double primary malignant tumors of female reproductive system primarily treated in Beijing Obstetrics and Gynecology Hospital, Capital Medical University from January 1, 2010 to December 31, 2020 were retrospectively collected. The age, symptoms, tumor stage, tumor type, treatment and prognosis of patients were collected and followed up. Results: (1) The number of patients with gynecological tumors in our hospital increased year by year in the past 11 years. A total of 8 987 patients with gynecological malignant tumors were firstly diagnosed and cured in our hospital, including 3 474 cases of cervical cancer, 3 484 cases of endometrial cancer, 1 329 cases of ovarian malignancies, 171 cases of fallopian tube cancer, 182 cases of uterine sarcoma, 42 cases of vaginal cancer, 192 cases of vulvar cancer, 110 cases of trophoblastic tumor and 3 cases of other gynecological malignancies. The top three cancers were endometrial cancer, cervical cancer and ovarian malignancies. (2) There were 23 patients identified with simultaneous double primary gynecological tumors in the past 11 years, accounting for 0.26% (23/8 987) of female malignant tumors. There were 3 cases of cervical cancer complicated with endometrial cancer, 3 cases of cervical cancer complicated with ovarian cancer, 16 cases of endometrial cancer combined with ovarian cancer, and 1 patient with endometrial cancer combined with fallopian tube cancer. (3) All 23 patients underwent surgical treatment. According to the first diagnosis of the tumor, the surgical methods included cervical cancer radical surgery, endometrial cancer staging surgery and ovarian cancer cytoreductive surgery. After operation, radiotherapy and chemotherapy were supplemented according to the results of pathological examination and tumor staging. (4) The age of 23 patients ranged from 28 to 66 years, with an average age of (49.4±9.7) years. All patients had vaginal bleeding or conscious pelvic mass as their main clinical manifestation. The clinical stage was found in 7 patients (30%, 7/23) with advanced gynecological cancer (stage Ⅲ-Ⅳ), and 16 patients (70%, 16/23) with early stage gynecological cancer (stage Ⅰ-Ⅱ). According to the nonspecific tumor markers, 13 patients (57%, 13/23) had elevated CA125 and CA199. (5) Among the 23 patients, 1 case was uncontrolled and 3 cases recurred during the follow-up period, and the sites of uncontrolled or recurred were all located in the abdominopelvic cavity. Three cases died. Among the 3 patients who died, 1 patient was an uncontrolled patient, whose tumor type was cervical adenosquamous cell carcinoma combined with ovarian clear cell adenocarcinoma. The overall survival time was 19 months with postoperative supplementary radiotherapy and chemotherapy. There were 2 recurrent patients, and the tumor types were endometrioid carcinoma complicated with high-grade serous ovarian carcinoma and ovarian endometrioid carcinoma, respectively. After surgery, all patients received supplementary chemotherapy and recurred 60 and 21 months after surgery, respectively, and the overall survival time was 78 and 28 months, respectively. Another patient recurred 43 months after surgery, and survived with tumor for 14 months after recurrence. The remaining 19 patients were tumor-free and were still being followed up. Conclusions: There are no specific markers for simultaneous double primary gynecological malignant tumors. The most common clinical symptoms are vaginal bleeding or pelvic mass. The treatment principle of simultaneous double primary gynecological malignant tumor is the same as that of single gynecological malignant tumor, but need to be taken into account the characteristics of two tumors. Surgery is the main treatment method, and radiotherapy and chemotherapy play an important auxiliary role. The prognosis of simultaneous double primary gynecological malignancies is related to the late stage of the two malignancies.

Ovarian Endometrioid and Clear Cell Carcinomas with Low Prevalence of Microsatellite Instability: A Unique Subset of Ovarian Carcinomas Could Benefit from Combination Therapy with Immune Checkpoint Inhibitors and Other Anticancer Agents.

Ovarian cancer has the highest mortality rate among all gynecological malignancies; therefore, a novel treatment strategy is needed urgently. Utilizing immune checkpoint inhibitors has been considered for microsatellite instability (MSI)-high (MSI-H) tumors. However, the prevalence of MSI-H tumors in ovarian endometrioid and clear cell carcinomas remains unclear. Here, polymerase chain reaction was used to analyze 91 cases of ovarian endometrioid and clear cell carcinomas for the MSI status and the relationship between MSI-H, immune checkpoint molecules, and clinicopathological factors (including patient survival). Only 5 of 91 (5%) cases were MSI-H endometrioid carcinomas. In these cases, CD-8 expression was significantly higher (p = 0.026), confirming an enhanced immune response. From the survival curve, no statistical correlations were found between the MSI-H group and the microsatellite stable (MSS) group; however, the MSS group trended towards better progression-free survival than the MSI-H group (p = 0.056). Patients with PD-L1 expression had shorter overall survival than those without (p = 0.022). Thus, MSI-H is a rare event and not a favorable prognostic factor in ovarian endometrioid and clear cell carcinomas. Thus, to improve the prognosis of ovarian endometrioid carcinoma and clear cell carcinomas, a combination therapy of immune checkpoint inhibitors and other molecular targeted therapies may be required.

TCGA molecular classification in endometriosis-associated ovarian carcinomas: Novel data on clear cell carcinoma

BackgroundClear cell and endometrioid ovarian carcinomas (OCC and OEC, respectively) have a presumed origin in endometriosis and share molecular alterations with each other and with their endometrial counterparts. The Cancer Genome Atlas (TCGA)-based molecular classification stratifies endometrial carcinomas into four categories: POLE mutated (POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP) with divergent prognoses. The subsequent studies are indicative that this TCGA classification has some value in OEC, but the knowledge related to OCC is limited. MethodsEndometrial carcinoma molecular classification was evaluated and compared in a large series of OCCs (n = 115) and OECs (n = 158). POLE mutation analysis and tissue microarray-based immunohistochemistry for mismatch repair and p53 proteins were performed. ResultsThe distribution to the molecular groups was as follows: POLEmut 0.9%/3.2%, MMRd 3.5%/6.3%, p53abn 20%/30%, and NSMP 76%/60% in OCCs/OECs, respectively. The proportion of NSMP tumors was the largest in both histological types and significantly higher in OCC than OEC (p = 0.009). The molecular classification correlated significantly with DSS in both OCCs and OECs (p < 0.001 and p = 0.009, respectively), and with DFS in OCCs (p = 0.001). POLEmut and MMRd OCCs carried excellent prognosis, whereas MMRd OECs presented with poorer outcome. The p53abn group was associated with the poorest prognosis in both tumor types, particularly emphasized in OCCs. ConclusionsTCGA molecular classification associated with patient outcome in both histotypes, and the difference in prognosis between the molecular groups was even more marked in OCC. The large amount of NSMP tumors highlights the need for further studies.

Evaluation of Saccharomyces cerevisiae -like 1 (SEC14L1) in Gynecologic Malignancies Shows Overexpression in Endometrial Serous Carcinoma.

Saccharomyces cerevisiae -like 1 ( SEC14L1 ) is a member of the SEC14 family and is involved in liposoluble vitamin transfer, and in a large cohort of breast cancer cases, was one of the genes most significantly associated with lymphovascular invasion (LVI), and had a significant relationship with human epidermal growth factor receptor 2 status, survival, and histologic grade. In this study, 111 separate gynecologic tumors were studied for SEC14L1 protein expression, including: uterine adenosarcoma, ovarian clear cell carcinoma, endometrial stromal sarcoma, endometrioid carcinoma of the uterus, high-grade serous carcinoma, ovarian endometrioid carcinoma, uterine leiomyosarcoma, low-grade serous carcinoma, uterine carcinosarcoma, and uterine serous carcinoma (USC). Overall, LVI was noted in 31/111 (28%) cases, highest in uterine carcinosarcoma (5/11; 45%), high-grade serous carcinoma (9/21; 43%), and ovarian clear cell carcinoma (4/10; 40%). SEC14L1 was positive in 25/111 (23%) cases; the highest percentage and only statistically significant finding by tumor type was USC at 9/12 (75%) cases positive. No relation between LVI or survival and SEC14L1 expression was noted. The relation between USC, a tumor known to show human epidermal growth factor receptor 2 overexpression and SEC14L1 is a novel finding, the significance of which warrants further study.

Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells

Deubiquitinases (DUBs) mediate the removal of ubiquitin from diverse proteins that participate in the regulation of cell survival, DNA damage repair, apoptosis and drug resistance. Previous studies have shown an association between activation of cell survival pathways and platinum-drug resistance in ovarian carcinoma cell lines. Among the strategies available to inhibit DUBs, curcumin derivatives appear promising, thus we hypothesized their use to enhance the efficacy of cisplatin in ovarian carcinoma preclinical models. The caffeic acid phenethyl ester (CAPE), inhibited ubiquitin-specific protease 8 (USP8), but not proteasomal DUBs in cell-free assays. When CAPE was combined with cisplatin in nine cell lines representative of various histotypes a synergistic effect was observed in TOV112D cells and in the cisplatin-resistant IGROV-1/Pt1 variant, both of endometrioid type and carrying mutant TP53. In the latter cells, persistent G1 accumulation upon combined treatment associated with p27kip1 protein levels was observed. The synergy was not dependent on apoptosis induction, and appeared to occur in cells with higher USP8 levels. In vivo antitumor activity studies supported the advantage of the combination of CAPE and cisplatin in the subcutaneous model of cisplatin-resistant IGROV-1/Pt1 ovarian carcinoma as well as CAPE activity on intraperitoneal disease. This study reveals the therapeutic potential of CAPE in cisplatin-resistant ovarian tumors as well as in tumors expressing USP8.

Role of serum microRNAs as biomarkers for endometriosis, endometrioid carcinoma of ovary & endometrioid endometrial cancer.

Accurate and early diagnosis is imperial in the management of endometriosis, endometrioid carcinoma of ovary (ECO) and endometrioid endometrial cancer (EC), yet there are no definitive diagnostic methods available for these diseases. Therefore, the present study was aimed to evaluate the diagnostic potential of differentially expressed miRNAs in serum samples of women with endometriosis, ECO and EC to establish them as diagnostic biomarkers. Blood samples (5 ml) were obtained from 40 patients (n=10/study group) undergoing laparoscopy/laparotomy/hysterectomy. miRNA-rich RNA was extracted from the serum samples, and quantitative real-time (qRT)-PCR was performed to check the expression levels of miR-16, miR-99b, miR-20a, miR-145, miR-143 and miR-125a in all the samples. Receiver operating characteristic (ROC) curve analysis was done to check the diagnostic potential. In endometriosis, miR-16 was downregulated (P<0.05) whereas miR-99b, miR-125a, miR-143 and miR-145 were upregulated (P<0.05). In ECO group, downregulated expression of miR-16 and miR-125a (P<0.05) was observed, whereas miR-99b, miR-143 and miR-145 were upregulated (P<0.05). In endometrioid EC, miR-16, miR-99b, miR-125 and miR-145 were downregulated (P<0.05), whereas miR-143 was upregulated (P<0.05). ROC curve analysis showed that, for endometriosis, miR-99b, miR-125a, miR-143 and miR-145 served as diagnostic markers. miR-145 showed diagnostic power for ECO, and for endometrioid EC, miR-16, miR-99b, miR-125a and miR-145 showed diagnostic potential. The present findings suggested that certain circulating miRNAs (miB99b, miR-16, miR-125a, miR-145) might act as indicators and discriminators of endometriosis and endometrioid subtypes of EC and ovarian cancer and might serve as potential biomarkers for early diagnosis and management of these debilitating diseases.

Prognostic role of overexpressed Bromodomain and extra-terminal family in ovarian cancer.

Background: BET family proteins have a role as epigenetic readers to accelerate the transcription of target genes. Several studies have shown that the BET protein family played important roles in several biological processes. Although, the prognostic influence of individual BET genes family in ovarian cancer patients remains unclear.Methods: We investigated BET mRNA prognostic roles subtypes in ovarian cancer patients by means of the KM plotter database. The BET mRNA expression and protein in cancer and normal ovarian cells was determined using qRTPCR and western blot. We used the HPA database to look at the protein expression profiles in normal and cancer tissues for this study.Results: Among BET members, mRNA expression BRD2 showed improve OS in all the ovarian malignancy patients, serous patients, stage III and IV, grade II and grade III, TP53 mutated ovarian cancer patients, as well as all patients treated with Platin based chemotherapy. As for BRD3, we found that BRD3 expression was related to better OS in endometrioid ovarian carcinoma and stage III+IV ovarian carcinoma patients, as well as all patients managed with Taxol and concurrent Taxol+Platin based chemotherapy. In addition, BRDT was associated with better OS in all ovarian carcinoma patients, grade I and grade III, all clinical stage (I+II, III+IV) patients, as well as all patients cured with Taxol and concurrent Taxol+Platin chemotherapy.Conclusion: We conclude that high expression of BRD2, BRD3, and BRDT predicted a better prognosis. mRNA expression of BET family is considerably associated with the prognosis of ovarian carcinoma and individual BET family gene could act as a predictive prognostic indicator in ovarian carcinoma.

Frequency and clinical features of deficient mismatch repair in ovarian clear cell and endometrioid carcinoma.

ObjectiveTo clarify the frequency of deficient mismatch repair (dMMR) in Japanese ovarian cancer patients, we examined microsatellite instability (MSI) status and immunohistochemistry (IHC) subtypes, including endometrioid carcinoma (EMC), clear cell carcinoma (CCC), or a mixture of both (Mix).MethodsWe registered 390 patients who were diagnosed with EMC/CCC/Mix between 2006 and 2015 and treated at seven participating facilities. For 339 patients confirmed eligible by the Central Pathological Review Board, MSI, IHC, and MutL homolog 1 methylation analyses were conducted. The tissues of patients with Lynch syndrome (LS)-related cancer histories, such as colorectal and endometrial cancer, were also investigated.ResultsMSI-high (MSI-H) status was observed in 2/217 CCC (0.9%), 10/115 EMC (8.7%), and 1/4 Mix (25%). Additionally, loss of MMR protein expression (LoE-MMR) was observed in 5/219 (2.3%), 16/115 (14.0%), and 1/4 (25%) patients with CCC, EMC, and Mix, respectively. Both MSI-H and LoE-MMR were found significantly more often in EMC (p<0.001). The median (range) ages of patients with MMR expression and LoE-MMR were 54 (30–90) and 46 (22–76) (p=0.002), respectively. In the multivariate analysis, advanced stage and histological type were identified as prognostic factors.ConclusionThe dMMR rate for EMC/CCC was similar to that reported in Western countries. In Japan, it is assumed that the dMMR frequency is higher because of the increased proportion of CCC.

The effect of complete surgical staging and adjuvant chemotherapy on survival in stage I, grade 1 and 2 endometrioid ovarian carcinoma

ObjectivesTo assess the effect of complete surgical staging and adjuvant chemotherapy on survival in stage I, low grade endometrioid ovarian cancer.MethodsThis retrospective study was conducted at two cancer centers from...

Pathways endometriosis associated ovarian cancer, a histological origin?

Endometrioid ovarian carcinoma (EnOC) and ovarian clear cell carcinoma (OCCC) are the most common endometriosis-associated ovarian cancer (EAOC) histologies. Literature suggests possible dichotomous pathways for cancer that arise from endometriosis verses those that do not, however it is not clearly defined and differences remain between histological subtypes. Additionally, the impact of endometriosis on prognosis in EAOC is varied. We aimed to explore the differences of patients with EnOC and OCCC with and without a concomitant diagnosis of endometriosis.

Genomic mutation features identify distinct BRCA-associated mutation characteristics in endometrioid carcinoma and endometrioid ovarian carcinoma

Although endometrioid carcinoma (EC) and endometrioid ovarian carcinoma (EnOC) display similar pathological features, their molecular characteristics remain to be determined. Somatic mutation data from 2777 EC, 423 EnOC, and 57 endometriosis patients from the Catalogue of Somatic Mutations in Cancer (COSMIC) dataset were analyzed and showed similar profiles with different mutation frequencies among them. By using 275 overlapping mutated genes, EC was clustered into two groups with different disease outcomes and different clinical characteristics. Although BRCA-associated mutation characteristics were identified in both EC and EnOC, the mutation frequencies of BRCA1 (P=0.0146), BRCA2 (P=0.0321), ATR (P=3.25E-11), RAD51 (P=3.95E-08), RAD1 (P=0.0003), TP53 (P=6.11E-33), and BRIP1 (P=2.90E-09) were higher in EnOC. Further analysis showed that EnOC cell lines with BRCA-associated mutation characteristics were more sensitive to poly ADP-ribose polymerase (PARP) inhibitors than EC cell lines, including olaparib, talazoparib, rucaparib, and veliparib. Moreover, based on BRCA-associated mutational and transcriptomic profiles, EC with BRCA-associated mutational burdens shows lower levels of immune cell infiltration, higher expression of immunosuppressive checkpoint molecules and worse prognosis than EC without BRCA mutation. Our study comprehensively analyzed the genome mutation features of EC and EnOC and provide insights into the molecular characteristics of EC and EnOC.

A novel human endometrial epithelial cell line for modeling gynecological diseases and for drug screening

Endometrium-related malignancies including uterine endometrioid carcinoma, ovarian clear cell carcinoma and ovarian endometrioid carcinoma are major types of gynecologic cancer, claiming more than 13,000 women's lives annually in the United States. In vitro cell models that recapitulate “normal” endometrial epithelial cells and their malignant counterparts are critically needed to facilitate the studies of pathogenesis in endometrium-related carcinomas. To achieve this objective, we have established a human endometrial epithelial cell line, hEM3, through immortalization and clonal selection from a primary human endometrium culture. hEM3 exhibits stable growth in vitro without senescence. hEM3 expresses protein markers characteristic of the endometrial epithelium, and they include PAX8, EpCAM, cytokeratin 7/8, and ER. hEM3 does not harbor pathogenic germline mutations in genes involving DNA mismatch repair (MMR) or homologous repair (HR) pathways. Despite its unlimited capacity of in vitro proliferation, hEM3 cells are not transformed, as they are not tumorigenic in immunocompromised mice. The cell line is amenable for gene editing, and we have established several gene-specific knockout clones targeting ARID1A, a tumor suppressor gene involved in the SWI/SNF chromatin remodeling. Drug screening demonstrates that both HDAC inhibitor and PARP inhibitor are effective in targeting cells with ARID1A deletion. Together, our data support the potential of hEM3 as a cell line model for studying the pathobiology of endometrium-related diseases and for developing effective precision therapies.This study describes the characterization of a human endometrial epithelial cell line, hEM3. hEM3 is not transformed, can grow organoids, and does not harbor pathogenic mutations in genes involving DNA mismatch repair (MMR). hEM3 with ARID1A knockout has been generated for drug screening in an ARID1A-deficient and MMR-proficient context. In conclusion, hEM3 can be a model for studying endometrial pathogenesis.

Clinical factors and biomarker profiles associated with patient outcome in endometrioid ovarian carcinoma - Emphasis on tumor grade

ObjectiveThe role of clinicopathological factors and molecular markers in prognostic classification of endometrioid ovarian carcinoma (EnOC) is not established. Tumor grade is used in risk assessment, but the role of current 3-tier grading system has been challenged. MethodsClinicopathological factors and 12 immunohistochemical biomarkers (PR, ER, β-catenin, vimentin, ARID1A, HNF1-β, p53, p16, MIB-1, E-cadherin, c-erb-B2 and L1CAM) were analyzed as regards patient outcome in 215 contemporarily classified EnOCs. ResultsOf clinical parameters, grade and stage appeared as strong independent prognostic factors both for disease-free and disease-specific overall survival. Grades 1–3 distinguished clearly from each other in the survival analysis, whereas stages I-II and stages III-IV clustered with each other. PR, ER, nuclear β-catenin and vimentin positivity were associated with favorable overall outcome and clinical parameters, whereas abnormal expression of p53, overexpression of p16 and L1CAM positivity were associated with aggressive disease characteristics and poor survival. The frequency of good-prognosis markers PR and β-catenin gradually decreased and poor-prognosis markers p53, p16 and L1CAM gradually increased from grade 1–3. However, vimentin and ER were expressed at similar frequencies across different grades and presented with independent prognostic significance. ConclusionsWe found histological grade and disease stage, but not residual tumor, to be independent clinical prognostic factors in EnOC. A set of good-prognosis markers (PR, ER, β-catenin and vimentin) and poor-prognosis markers (p53, p16 and L1CAM) were identified. Our findings support continuation of the use of the 3-tier grading system for EnOC and provide clinically feasible IHC biomarkers for prognostic profiling.