The Protein Landscape of Mucinous Ovarian Cancer: Towards a Theranostic.
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ABSTRACT:
SUBMITTER: Youssef A
PROVIDER: S-EPMC8616050 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive/HER2-negative breast cancer (BC) characterized by tumor cells floating in lakes of mucin. We assessed the genomic landscape of 32 MCBs by whole-exome sequencing and/or RNA-sequencing. GATA3 (23.8%), KMT2C (19.0%), and MAP3K1 (14.3%) were the most frequently mutated genes in pure MCBs. In addition, two recurrent but not pathognomonic fusion genes, OAZ1-CSNK1G2 and RFC4-LPP, were detected in 3/31 (9.7%) and 2/31 (6.5%) samples, respectively. Compared with ER-positive/HER2-negative common forms of BC, MCBs displayed lower PIK3CA and TP53 mutation rates and fewer concurrent 1q gains and 16q losses. Clonal decomposition analysis of the mucinous and ductal components independently microdissected from five mixed MCBs revealed that they are clonally related and evolve following clonal selection or parallel evolution. Our findings indicate that MCB represents a genetically distinct ER-positive/HER2-negative form of BC.
| S-EPMC6624163 | biostudies-literature
Project description:ObjectiveMucinous borderline ovarian tumor (mucinous-BOT) and invasive well-differentiated mucinous ovarian cancer (mucinous-OC) are often histopathologically misclassified. The objective of this study was to examine differences in clinico-pathological characteristics and outcomes of these two entities.MethodsThis is a retrospective population-based study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2000. Stage I mucinous-BOTs and stage I well-differentiated mucinous-OC were compared for patient demographics, tumor characteristics, and outcomes. Propensity score matching and multivariable analysis were used to assess cause-specific survival (CSS).ResultsA total of 2130 mucinous-BOT and 581 mucinous-OC cases were examined for analysis. On multivariable analysis, women with mucinous-OC were more likely to be older, Eastern U.S. residents, and have undergone hysterectomy or lymphadenectomy compared to those with mucinous-BOT, and the number of women diagnosed with mucinous-OC decreased over time (all, P < 0.05). Mucinous-OCs were more likely to be stage T1c and have a smaller tumor size as compared to mucinous-BOT (both, adjusted-P < 0.05). After propensity score matching, women with mucinous-OC had significantly poorer CSS compared to those with mucinous-BOT on multivariable analysis (10-year rates: 92.7% versus 97.5%, adjusted-hazard ratio [HR] 2.03, P = 0.007). Similar results were observed among subgroups for reproductive age, stage T1a disease, large tumor, and unstaged cases (all, P < 0.05).ConclusionStage I mucinous-BOT and stage I invasive well-differentiated mucinous-OC have distinct differences in clinical characteristics and patient survival. The inability to conduct centralized pathology review in our study limits our conclusions given the recognized issue of misclassification of mucinous-BOT and mucinous-OC, but further highlights the importance of making the proper histopathological diagnosis for invasive cancer when the ovarian tumor is of mucinous histology.
| S-EPMC7523227 | biostudies-literature
Project description:BackgroundOvarian cancer is one of the most lethal cancers in women because it is often diagnosed at an advanced stage. The molecular markers investigated thus far have been unsatisfactory.MethodsWe performed whole-exome sequencing on the human ovarian cancer cell lines 3AO and ES2 and the normal ovarian epithelial cell line IOSE-80. Molecular markers of ovarian cancer were screened from shared mutation genes and copy number variation genes in the 6q21-qter region.ResultsWe found that missense mutations were the most common mutations in the gene (93%). The MUC12, FLG and MUC16 genes were highly mutated in 3AO and ES2 cells. Copy number amplification occurred mainly in 4p16.1 and 11q14.3, and copy number deletions occurred in 4q34.3 and 18p11.21. A total of 23 hub genes were screened, of which 16 were closely related to the survival of ovarian cancer patients. The three genes CCDC170, THBS2 and COL14A1 are most significantly correlated with the survival and prognosis of ovarian cancer. In particular, the overall survival of ovarian cancer patients with high CCDC170 gene expression was significantly prolonged (P < 0.001). The expression of CCDC170 in normal tissues was significantly higher than that in ovarian cancer tissues (P < 0.05), and its expression was significantly decreased in advanced ovarian cancer. Western blotting and immunofluorescence assays also showed that the expression of CCDC170 in ovarian cancer cells was significantly lower than that in normal cells (P < 0.001, P < 0.01).ConclusionsCCDC170 is expected to become a new diagnostic molecular target and prognostic indicator for ovarian cancer patients, which can provide new ideas for the design of antitumor drugs.
| S-EPMC10080944 | biostudies-literature
Project description:Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT-PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.
| S-EPMC2361366 | biostudies-literature
Project description:ObjectiveTo examine the association between postoperative chemotherapy and survival of women with stage IC mucinous ovarian cancer (MOC).MethodsComprehensive nationwide tumor registry data from the Commission on Cancer-accredited facilities in the United States from 2004 to 2014 were retrospectively examined. Women with stage IC MOC who underwent primary surgery followed by postoperative chemotherapy were compared to those who did not receive. Clinico-pathological factors associated with chemotherapy use, and overall survival associated with chemotherapy use were examined with multivariable models and propensity score inverse probability of treatment weighting (IPTW). External validation was performed by examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2014.ResultsThere were 532 (58.5%) women who received postoperative chemotherapy and 377 (41.5%) women who did not. On multivariable analysis, those with moderately-/poorly-differentiated tumors, large tumor size, and who underwent lymphadenectomy were more likely to receive postoperative chemotherapy whereas young women and those with capsule rupture alone were less likely to receive postoperative chemotherapy (all, P < 0.05). After IPTW, there was no difference in overall survival among women who received postoperative chemotherapy versus those who did not on multivariable analysis (adjusted 4-year rates: 85.8% versus 86.3%, adjusted-hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.60-1.31). Similarly, there was no benefit with chemotherapy regardless of patient age, tumor differentiation, performance of nodal dissection, and substage groups. Among 912 cases in the validation cohort (postoperative chemotherapy use, n = 520 [57.0%]), postoperative chemotherapy use was not associated with cause-specific survival (adjusted-HR 1.296, 95% CI 0.846-1.984, P = 0.233) or overall survival (adjusted-HR 1.131, 95% CI 0.849-1.508, P = 0.400).ConclusionPostoperative chemotherapy was received by fewer than 60% of women with stage IC MOC, and postoperative chemotherapy was not associated with improved survival.
| S-EPMC7534809 | biostudies-literature
Project description:Mucinous ovarian carcinoma (mEOC) represents a rare subtype of epithelial ovarian cancer, accounting for 3-4% of all ovarian carcinomas. The rarity of this tumor type renders both the preclinical and clinical research compelling. Very few preclinical in vitro and in vivo models exist. We here report the molecular, metabolic and pharmacological characterization of two patient derived xenografts (PDXs) from mEOC, recently obtained in our laboratory. These PDXs maintain the histological and molecular characteristics of the patient's tumors they derived from, including a wild type TP53. Gene expression analysis and metabolomics profile suggest that they differ from high grade serous/endometrioid ovarian carcinoma PDXs. The pharmacological characterization was undertaken testing the in vivo antitumor activity of both cytotoxic agents (cisplatin, paclitaxel, yondelis, oxaliplatin and 5-fluorouracile) and targeted agents (bevacizumab and lapatinib). These newly established mucinous PDXs do recapitulate mEOC and will be of value in the preclinical development of possible new therapeutic strategies for this tumor type.
| S-EPMC7061742 | biostudies-literature
Project description:For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA/PACT in oxaliplatin resistance was interrogated. We focused on PRKRA, a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA/PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin.
| S-EPMC6318044 | biostudies-literature
Project description:ObjectiveMucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents.MethodsWe analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166).ResultsMolecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184).ConclusionsAlthough genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
| S-EPMC7056511 | biostudies-literature
Project description:Elimination of cancer through early detection and treatment is the ultimate goal of cancer research and is especially critical for ovarian and other forms of cancer typically diagnosed at very late stages that have very poor response rates. Proteomics has opened new avenues for the discovery of diagnostic and therapeutic targets. Immunoproteomics, which defines the subset of proteins involved in the immune response, holds considerable promise for providing a better understanding of the early-stage immune response to cancer as well as important insights into antigens that may be suitable for immunotherapy. Early administration of immunotherapeutic vaccines can potentially have profound effects on prevention of metastasis and may potentially cure through efficient and complete tumor elimination. We developed a mass-spectrometry-based method to identify novel autoantibody-based serum biomarkers for the early diagnosis of ovarian cancer that uses native tumor-associated proteins immunoprecipitated by autoantibodies from sera obtained from cancer patients and from cancer-free controls to identify autoantibody signatures that occur at high frequency only in cancer patient sera. Interestingly, we identified a subset of more than 50 autoantigens that were also processed and presented by MHC class I molecules on the surfaces of ovarian cancer cells and thus were common to the two immunological processes of humoral and cell-mediated immunity. These shared autoantigens were highly representative of families of proteins with roles in key processes in carcinogenesis and metastasis, such as cell cycle regulation, cell proliferation, apoptosis, tumor suppression, and cell adhesion. Autoantibodies appearing at the early stages of cancer suggest that this detectable immune response to the developing tumor can be exploited as early-stage biomarkers for the development of ovarian cancer diagnostics. Correspondingly, because the T-cell immune response depends on MHC class I processing and presentation of peptides, proteins that go through this pathway are potential candidates for the development of immunotherapeutics designed to activate a T-cell immune response to cancer. To the best of our knowledge, this is the first comprehensive study that identifies and categorizes proteins that are involved in both humoral and cell-mediated immunity against ovarian cancer, and it may have broad implications for the discovery and selection of theranostic molecular targets for cancer therapeutics and diagnostics in general.
| S-EPMC2533805 | biostudies-literature
Project description:Despite advances in surgery and chemotherapy, the overall outcomes for patients with advanced ovarian cancer remain poor. Although initial response rates to platinum-based chemotherapy is about 60-80%, most patients will have recurrence and succumb to the disease. However, a DNA repair-directed precision medicine strategy has recently generated real hope in improving survival. The clinical development of PARP inhibitors has transformed lives for many patients with BRCA germline-deficient and/or platinum-sensitive epithelial ovarian cancers. Antiangiogenic agents and intraperitoneal chemotherapy approaches may also improve outcomes in patients. Moreover, evolving immunotherapeutic opportunities could also positively impact patient outcomes. Here we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in ovarian cancer.
| S-EPMC9762171 | biostudies-literature