Project description:Clear cell ovarian carcinoma (CCOC) is the second most common subtype of epithelial ovarian carcinoma. Late stage CCOC is not responsive to gold-standard chemotherapy and result in suboptimal outcome for patients. In-depth molecular insight is urgently needed to stratify the disease and drive therapeutic development. We conducted global proteomics in 192 cases of CCOC comparing to other epithelial ovarian carcinoma subtypes.
Project description:ARID1A, which encodes a component of the SWI/SNF chromatin-remodeling complex, is commonly mutated in ovarian clear cell carcinoma and many other cancer types. We used label-free LC-MS/MS to identify ARID1A-dependent proteome changes in ovarian clear cell carcinoma cell lines. In our first analysis, we compared ARID1A-wildtype ovarian clear cell carcinoma cell line OVCA429 with or without ARID1A CRISPR knockout. In a complementary analysis, we compared ARID1A-mutated ovarian clear cell carcinoma cell line OVISE with or without ARID1A overexpression using a tet-inducible promoter.
Project description:To investigate the microRNA profiles of ovarian clear cell carcinoma (OCCC), microRNA sequencing was performed using formalin-fixed, paraffin-embedded (FFPE) and fresh-frozen clinical samples. Moreover, patient-derived xenograft (PDX) tumors and cell lines were also investigated.
Project description:Ovarian cancer is a malignant gynecologic disease rarely diagnosed in the early stages. Among ovarian cancers, clear cell carcinoma has a poor prognosis due to its malignant potential. MicroRNAs (miRNAs) regulate gene expression in cells by suppressing the translation of the target gene or by degrading the target mRNA. They are also secreted from the cells in the blood, binding to the proteins or lipids and assisting in cell-cell communication. Hence, serum miRNAs can also be diagnostic biomarkers for ovarian cancer. This study investigated and identified specific miRNAs for ovarian clear cell carcinoma and compared them to those of ovarian endometrioma in healthy patients. CA125, an ovarian tumor marker, did not differ between patients with ovarian clear cell carcinoma, endometriosis, or healthy controls. Four miRNAs (miR-146a-5p, miR-191-5p, miR-484, and miR-574-3p) were analyzed. The miR-146a-5p and miR-191-5p expression levels were significantly increased in the serum samples from the patients with ovarian clear cell carcinoma compared to the healthy controls but not in the patients with endometriosis (P < 0.05). Furthermore, the bioinformatics analysis showed that CCND2 and NOTCH2 were the candidate target genes of miR 146a-5p and miR-191-5p. In conclusion, our results showed that miR 146a-5p and miR-191-5p might be useful as early and non-invasive diagnostic tools in ovarian clear cell carcinoma. These miRNAs can help in distinguishing between ovarian clear cell carcinoma and ovarian endometrioma. To the best of our knowledge, no studies have screened any candidates specifically for clear cell carcinoma.
Project description:Background: Recent data demonstrated efficacy of immune checkpoint inhibitors in advanced OCCC, but little is known about the immune microenvironment of these tumours and its impact on outcomes. We studied the expression of a panel of immune response genes in OCCC to identify the presence and prognostic relevance of irGES in these tumours. Methods: Immune response gene profiling was performed on 96 FFPE OCCC tumour samples with matched clinical outcomes, collected from the National University Hospital, Singapore between 2003 – 2016, using the nanoString nCounter PanCancer Immune Profiling Panel. Unsupervised hierarchical clustering analysis was performed to stratify OCCCs to derive the irGES profiles. Upregulation of specific genes of interest at the protein level and the status of mismatch repair (MMR) and ARID1A were validated using immunohistochemistry (IHC). Results: Total of 74/84 samples were successfully profiled. Median age at diagnosis was 53 yrs. 41 (55.4%) were stage 1, 7 (9.5%) stage 2, 24 (32.4%) Stage3, 2 (2.7%) stage 4. 64/74 (86.5%) of patients received adjuvant chemotherapy post debulking surgery with 38% recurrence rate (median PFS 27 months). Median follow up was 36 months. Based on irGES, 4 distinct molecular subgroups of OCCCs were identified. G1 was hallmarked by NK cell markers and PD-1 expression (PD-1 high), G2 by increased CTLA-4 expression, G3 by upregulation of genes associated with immunogenicity and antigen presentation, and G4 by increased levels of pro - angiogenic genes. The PD-1 high group was observed to have significantly poorer PFS (median PFS 20 months vs 68 months, p= 0.011) and a trend towards poorer OS when compared with G2/3/4 (median OS 38.8 months vs undefined, p = 0.0501). The pro - angiogenic (G4) carried the best prognosis (median PFS 108 months vs 26 months, p= 0.0515; median OS undefined, p= 0.0726). This difference in OS and PFS was consistently observed between stage 1 and non-stage 1 pts (hazard ratio 5.856 and 5.659, p < 0.0001, respectively). Significant correlation was observed between gene and protein expression of tumour PD-1, tumour and stromal PD-L1, and tumour IL-6 using IHC (p < 0.0001 for all comparisons). 6 (8.1%) pts were MMR deficient and there was no significant association between ARID1A and MMR expression across each irGES groups. Conclusion: OCCCs are heterogeneous and can be classified into 4 molecular subgroups based on their irGES profiles representing distinct clinicopathological characteristics and prognostic outcomes. If validated in larger datasets, these signatures may serve to guide clinical trial design and personalized treatment for OCCC pts.
Project description:Exploring the expression profile of ovarian clear cell carcinoma cancer cell subpopulations- derived tumors grown within a murine and a human cellular tissues.
Project description:We performed RNA Sequencing on eleven ovarian clear cell carcinoma and five uterine clear cell carcinoma patients to identify the unique transcriptional expression profiles of clear cell uterine and ovarian cancer, and investigates correlations with demographic factors and tumor characteristics, such as stage and PD-L1 immunohistochemical expression.