Dataset Information

Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

ABSTRACT: To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.

SUBMITTER: Chowdhury S

PROVIDER: S-EPMC10414761 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

Chowdhury Shrabanti S Kennedy Jacob J JJ Ivey Richard G RG Murillo Oscar D OD Hosseini Noshad N Song Xiaoyu X Petralia Francesca F Calinawan Anna A Savage Sara R SR Berry Anna B AB Reva Boris B Ozbek Umut U Krek Azra A Ma Weiping W da Veiga Leprevost Felipe F Ji Jiayi J Yoo Seungyeul S Lin Chenwei C Voytovich Uliana J UJ Huang Yajue Y Lee Sun-Hee SH Bergan Lindsay L Lorentzen Travis D TD Mesri Mehdi M Rodriguez Henry H Hoofnagle Andrew N AN Herbert Zachary T ZT Nesvizhskii Alexey I AI Zhang Bing B Whiteaker Jeffrey R JR Fenyo David D McKerrow Wilson W Wang Joshua J Schürer Stephan C SC Stathias Vasileios V Chen X Steven XS Barcellos-Hoff Mary Helen MH Starr Timothy K TK Winterhoff Boris J BJ Nelson Andrew C AC Mok Samuel C SC Kaufmann Scott H SH Drescher Charles C Cieslik Marcin M Wang Pei P Birrer Michael J MJ Paulovich Amanda G AG

Cell 20230801 16

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. ...[more]

PMID: 37541199

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Project description:<a href="https://pdc.esacinc.com/pdc/browse/filters/study_name:TCGA_Ovarian_JHU_Glycoproteome|TCGA_Ovarian_JHU_Proteome|TCGA_Ovarian_PNNL_Proteome|TCGA_Ovarian_PNNL_Phosphoproteome_Velos_Qexatvive" target="_blank">Explore This Study at the NCI Proteomic Data Commons</a><a href="http://www.ncbi.nlm.nih.gov/pubmed/27372738" target="_blank">Zhang H, Liu T, Zhang Z, Payne SH, Zhang B, McDermott JE et al., Cell (2016), DOI: 10.1016/j.cell.2016.05.069, Published online June 29, 2016.</a>To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC.Information on the complete TCGA Ovarian Serous Cystadenocarcinoma (OV) cohort can be found <a href="https://portal.gdc.cancer.gov/projects/TCGA-OV" target="_blank">here</a>. The Cancer Genome Atlas Research Network published on the Genomic characterization of the OV cohort in <a href="http://www.ncbi.nlm.nih.gov/pubmed/21720365" target="_blank">Nature</a> on June 30, 2011Genomic data for the 174 TCGA samples used in the CPTAC Proteome study can be downloaded from <a href="https://portal.gdc.cancer.gov/legacy-archive/search/f?filters=%7B%22op%22:%22and%22,%22content%22:%5B%7B%22op%22:%22in%22,%22content%22:%7B%22field%22:%22cases.project.program.name%22,%22value%22:%5B%22TCGA%22%5D%7D%7D,%7B%22op%22:%22in%22,%22content%22:%7B%22field%22:%22cases.project.project_id%22,%22value%22:%5B%22TCGA-OV%22%5D%7D%7D%5D%7D" target="_blank">here</a>.Peptide-Spectrum-Matches and Protein Reports from the CPTAC Common Data Analysis Pipeline (CDAP) can be downloaded from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S020" target="_blank">here</a>.<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S026">https://cptac-data-portal.georgetown.edu/cptac/s/S026</a> on 08/28/19</li><li>Dataset source: <a href="https://pdc.esacinc.com/pdc/browse/filters/study_name:TCGA_Ovarian_JHU_Glycoproteome|TCGA_Ovarian_JHU_Proteome|TCGA_Ovarian_PNNL_Proteome|TCGA_Ovarian_PNNL_Phosphoproteome_Velos_Qexatvive" target="_blank">https://pdc.esacinc.com/pdc/browse/filters/study_name:...</a></li></ul>

Project description:PurposeOvarian cancer is the leading cause of gynecologic cancer-related death worldwide. Early diagnosis of ovarian cancer can significantly improve patient prognosis. Hence, there is an urgent need to identify key diagnostic and prognostic biomarkers specific for ovarian cancer. Because high-grade serous ovarian cancer (HGSOC) is the most common type of ovarian cancer and accounts for the majority of deaths, we identified potential biomarkers for the early diagnosis and prognosis of HGSOC.MethodsSix datasets (GSE14001, GSE18520, GSE26712, GSE27651, GSE40595, and GSE54388) were downloaded from the Gene Expression Omnibus database for analysis. Differentially expressed genes (DEGs) between HGSOC and normal ovarian surface epithelium samples were screened via integrated analysis. Hub genes were identified by analyzing protein-protein interaction (PPI) network data. The online Kaplan-Meier plotter was utilized to evaluate the prognostic roles of these hub genes. The expression of these hub genes was confirmed with Oncomine datasets and validated by quantitative real-time PCR and Western blotting.ResultsA total of 103 DEGs in patients with HGSOC-28 upregulated genes and 75 downregulated genes-were successfully screened. Enrichment analyses revealed that the upregulated genes were enriched in cell division and cell proliferation and that the downregulated genes mainly participated in the Wnt signaling pathway and various metabolic processes. Ten hub genes were associated with HGSOC pathogenesis. Seven overexpressed hub genes were partitioned into module 1 of the PPI network, which was enriched in the cell cycle and DNA replication pathways. Survival analysis revealed that MELK, CEP55 and KDR expression levels were significantly correlated with the overall survival of HGSOC patients (P < 0.05). The RNA and protein expression levels of these hub genes were validated experimentally.ConclusionBased on an integrated analysis, we propose the further investigation of MELK, CEP55 and KDR as promising diagnostic and prognostic biomarkers of HGSOC.

Dataset Information

Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

Publications

Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

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