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Molecular Profiles of Serum-Derived Extracellular Vesicles in High-Grade Serous Ovarian Cancer.

ABSTRACT: Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.

SUBMITTER: Zhao L

PROVIDER: S-EPMC9330879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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molecular profiles of serum-derived extracellular vesicles in high-grade serous ovarian cancer

Project description:Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have response enabling interval cytoreductive surgery. Clinically useful predictive biomarkers for such distinctions are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated them with therapeutic outcomes in patients with HGSC.

| EGAS00001006350 | EGA

Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts.

Project description:IntroductionImprovement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses.MethodsWe generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγ(null) recipient mice, completed molecular annotation and assessed platinum sensitivity.ResultsThe success rate of xenografting was 83%. Of ten HG-SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression-free interval ≥ 100 d, n = 4), resistant (progression-free interval <100 d, n = 3) or refractory (n = 3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2).ConclusionsBecause PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG-SOC.

| S-EPMC4400120 | biostudies-literature

Differential Expression Profiles and Function Prediction of Transfer RNA-Derived Fragments in High-Grade Serous Ovarian Cancer.

Project description:BackgroundThe present study is aimed at providing systematic insight into the composition and expression of transfer RNA (tRNA) derivative transcription in high-grade serous ovarian cancer (HGSOC).MethodstRNA derivative expression profiles in three pairs of HGSOC and adjacent normal ovarian tissues were conducted by tRNA-derived small RNA fragment (tRF) and tRNA half (tiRNA) sequencing. The differentially expressed tRFs and tiRNAs between HGSOC and paired adjacent normal samples were screened. The targeted genes of differentially expressed tRFs and tiRNAs were screened. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) of target genes of tRFs and tiRNAs were analyzed.ResultsThere are a total of 20 significantly upregulated and 15 significantly downregulated tRFs and tiRNAs between the cancer group and the paracarcinoma group. The upregulated tRFs and tiRNAs are mucin-type O-glycan biosynthesis, glycosphingolipid biosynthesis, the glucagon signaling pathway, the AMPK signaling pathway, maturity-onset diabetes of the young, glycosphingolipid biosynthesis, the insulin signaling pathway, insulin resistance, leukocyte transendothelial migration, starch, and sucrose metabolism. The downregulated tRFs and tiRNAs are other glycan degradation, vitamin digestion and absorption, fatty acid elongation, and biosynthesis of unsaturated fatty acids.ConclusionsThere are significantly expressed tRFs and tiRNAs in HGSOC tissues, and these may provide potential diagnostic biomarkers and therapeutic targets for HGSOC.

| S-EPMC8028742 | biostudies-literature

Consensus on Molecular Subtypes of High-Grade Serous Ovarian Carcinoma.

Project description:Purpose: The majority of ovarian carcinomas are of high-grade serous histology, which is associated with poor prognosis. Surgery and chemotherapy are the mainstay of treatment, and molecular characterization is necessary to lead the way to targeted therapeutic options. To this end, various computational methods for gene expression-based subtyping of high-grade serous ovarian carcinoma (HGSOC) have been proposed, but their overlap and robustness remain unknown.Experimental Design: We assess three major subtype classifiers by meta-analysis of publicly available expression data, and assess statistical criteria of subtype robustness and classifier concordance. We develop a consensus classifier that represents the subtype classifications of tumors based on the consensus of multiple methods, and outputs a confidence score. Using our compendium of expression data, we examine the possibility that a subset of tumors is unclassifiable based on currently proposed subtypes.Results: HGSOC subtyping classifiers exhibit moderate pairwise concordance across our data compendium (58.9%-70.9%; P < 10-5) and are associated with overall survival in a meta-analysis across datasets (P < 10-5). Current subtypes do not meet statistical criteria for robustness to reclustering across multiple datasets (prediction strength < 0.6). A new subtype classifier is trained on concordantly classified samples to yield a consensus classification of patient tumors that correlates with patient age, survival, tumor purity, and lymphocyte infiltration.Conclusions: A new consensus ovarian subtype classifier represents the consensus of methods and demonstrates the importance of classification approaches for cancer that do not require all tumors to be assigned to a distinct subtype. Clin Cancer Res; 24(20); 5037-47. ©2018 AACR.

| S-EPMC6207081 | biostudies-literature

Project description:Ovarian and endometrial high-grade serous carcinomas (HGSCs) have similar clinical and pathological characteristics; however, exhaustive protein expression profiling of these cancers has yet to be reported.We performed protein expression profiling on 14 cases of HGSCs (7 ovarian and 7 endometrial) and 18 endometrioid carcinomas (9 ovarian and 9 endometrial) using iTRAQ-based exhaustive and quantitative protein analysis.We identified 828 tumour-expressed proteins and evaluated the statistical similarity of protein expression profiles between ovarian and endometrial HGSCs using unsupervised hierarchical cluster analysis (P<0.01). Using 45 statistically highly expressed proteins in HGSCs, protein ontology analysis detected two enriched terms and proteins composing each term: IMP2 and MCM2. Immunohistochemical analyses confirmed the higher expression of IMP2 and MCM2 in ovarian and endometrial HGSCs as well as in tubal and peritoneal HGSCs than in endometrioid carcinomas (P<0.01). The knockdown of either IMP2 or MCM2 by siRNA interference significantly decreased the proliferation rate of ovarian HGSC cell line (P<0.01).We demonstrated the statistical similarity of the protein expression profiles of ovarian and endometrial HGSC beyond the organs. We suggest that increased IMP2 and MCM2 expression may underlie some of the rapid HGSC growth observed clinically.

| S-EPMC4782211 | biostudies-literature

Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma.

Project description:While high-grade serous ovarian carcinoma (HGSOC) is the most common histologic subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants [by DNA next-generation sequencing (NGS) using a 50 gene Ion Torrent panel] and gene expression (using the NanoString PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT). NGS was performed on plasma cell free DNA (cfDNA) on a select group of patients (n = 14) to assess the utility of using cfDNA to monitor these changes. A total of 86 genes had significant changes in RNA expression after NACT. Thirty-eight genetic variants (including SNPs) from 6 genes were identified in tumors pre-NACT, while 59 variants from 19 genes were detected in the cfDNA. The number of DNA variants were similar after NACT. Of the 59 variants in the plasma pre-NACT, only 6 persisted, whereas 33 of 38 specific variants in the tumor DNA remained unchanged. Pathway analysis showed the most significant alterations in the cell cycle and DNA damage pathways.Implications: Gene expression profiles at the time of interval debulking provide additional genetic information that could help impact treatment decisions after NACT; although, continued collection and analysis of matched tumor and cfDNA from multiple time points are needed to determine the role of cfDNA in the management of HGSOC. Mol Cancer Res; 16(5); 813-24. ©2018 AACR.

| S-EPMC6497146 | biostudies-literature

Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome.

Project description:PURPOSE:High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. EXPERIMENTAL DESIGN:We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). RESULTS:LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. CONCLUSIONS:Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors.

| S-EPMC4205235 | biostudies-literature

microRNA profiling of serum microRNA from high grade serous ovarian carcinoma

Project description:High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic neoplasm, with five-year survival rate below 30%. Early disease detection is of utmost importance to improve the cure rate of HGSOC. Liquid biopsies are now becoming a new paradigm to develop novel biomarkers with diagnostic and prognostic purposes. The focus of this study was to detect the levels of circulating miRNAs in tissues and sera from patients with HGSOC and to evaluate their diagnostic value. To this end, an array-based discovery platform, followed by an innovative statistical approach of data normalization, was exploited, to identify miRNA species selectively expressed in serum of patients with HGSOC. Sera from 106 high grade serous ovarian carcinoma (HGSOC) and 24 healthy controls were used for profiling serum microRNA using a modified version of a commercially available microarray, with the aim of identifying differentially expressed microRNA between tumor patients and healthy controls.

2017-01-30 | E-MTAB-4667 | biostudies-arrayexpress

Hormone receptor expression profiles differ between primary and recurrent high-grade serous ovarian cancers.

Project description:Hormone receptor status assessment is necessary for selecting cancer patients who might potentially benefit from endocrine therapy. To determine whether hormone receptor status changes during tumor progression, we retrospectively examined 107 high-grade serous ovarian cancer (HGSC) patients with paired primary and recurrent tumor specimens. Hormone receptor expression discordance rates between primary and recurrent tumors were as follows: estrogen receptor (ER) 34.9%, progesterone receptor (PR) 12.4%, androgen receptor (AR) 41.7%, follicle stimulating hormone receptor 46.6%, luteinizing hormone receptor 50.5%, and gonadotropin releasing hormone receptor 20.0%. Hormone receptor discordance was not associated with patient survival. The proportion of the PR-ER+AR- subgroup, which exhibited the worst prognosis, was higher in recurrent than primary tumor specimens. Our study demonstrated that paired primary and recurrent HGSC specimens exhibit differing hormone receptor profiles. Thus, to most effectively identify patient-specific therapies, biomarker status re-assessment is required for recurrent patients.

| S-EPMC5464832 | biostudies-literature

Molecular classification and immunologic characteristics of immunoreactive high?grade serous ovarian cancer

Project description:Abstract High?grade serous ovarian cancer (HGS?OvCa) is one of the most lethal gynaecological malignancies. Molecular classification identified an immunoreactive subtype of HGS?OvCa; however, the immunologic characteristics of immunoreactive HGS?OvcA remain unclear. In this study, 121 immunoreactive HGS?OvCa samples were identified from a meta?analysis of 5 large transcriptome profiling data sets using a cross?platform immunoreactive HGS?OvCa subgroup?specific classifier. By comparing the gene expression profiles of immunoreactive HGS?OvCa samples and normal tissues, 653 differentially expressed genes (DEGs) were identified. KEGG pathway analysis revealed that the leukocyte transendothelial migration pathways were significantly enriched in the immunoreactive HGS?OvCa. Protein?protein interaction analysis identified a module that showed strong involvement of the immune?related chemokine signalling pathway. Moreover, the GSEA enrichment analysis showed a T?cell subgroup and M1 macrophages were significantly enriched in immunoreactive OvCa compared with normal samples. Macrophage infiltration levels were significantly elevated in immunoreactive HGS?OvCa compared with other OvCa subtypes. In addition, expression of immune checkpoint molecules VTCN1 and IDO1 was significantly increased in immunoreactive HGS?OvCa. In summary, our results suggest that the immunoreactive HGS?OvCa has unique molecular characteristics and a tumour?associated immune microenvironment featured by increased infiltration of macrophages, rather than lymphocytes. VTCN1 could be potential targets for the treatment of immunoreactive HGS?OvCa.

| S-EPMC7348149 | biostudies-literature

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