Dataset Information

Extensive Three-Dimensional Intratumor Proteomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens

ABSTRACT: Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten high-grade serous ovarian carcinomas (HGSOC) and analyzed by mass spectrometry. Unsupervised analyses of protein abundance data revealed independent clustering of enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering driven by overall tumor “purity”. Comparing these data to previously defined prognostic HGSOC molecular subtypes revealed protein expression from tumor epithelium correlated with the differentiated subtype, whereas stromal proteins correlated with the mesenchymal subtype. Protein abundance in tumor epithelium and stroma exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial tumor microenvironment protein heterogeneity that directly bears on prognostic signatures, biomarker discovery, and cancer pathophysiology, and underscore the need to enrich cellular subpopulations for expression profiling.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Ovarian Serous Carcinoma Cell, Stromal Cell

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Brian Hood

LAB HEAD: Thomas P. Conrads, PhD

PROVIDER: PXD026570 | Pride | 2021-07-01

REPOSITORIES: Pride

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Project description:A data set of normal epithelium, serous ovarian surface epithelial-stromal tumors (benign and type II malignancies), stroma distal to tumor, and stroma adjacent to tumor (50 samples total). Additional cel files are included which represent replicate sampling from patients, and cel files that failed quality control but may be bioinformatically interesting. Additional replicate or failed cel files were not included in the final analysis (and so these samples were not included in the matrix). Background: Ovarian cancer is the most lethal gynecologic cancer in the United States. If caught in early stages, patient survival rate can reach 94%, when diagnosed at late stages survival rates drop to 28%. Correct diagnosis depends on the presence of definite symptoms: while ~90% of diagnosed ovarian cancers have symptoms, they tend to be unfocused and subacute. A definitive and early molecular signature of disease is thus desired. To further progress towards this goal, we present an Affymetrix™ human exon array data set measuring ovarian tumor expression, assembled using best practices. Method: Samples were collected from patients with benign and malignant (type II) serous ovarian surface epithelial-stromal tumors. Normal epithelium, tumor, stroma adjacent to tumor, and distal stroma were selected based on histopathology, and isolated using laser capture microdissection. Nugen products were used to perform random-primed mRNA amplification procedures (for full transcript capture) before hybridization to Affymetrix exon chips. Tumor expression and paracrine signaling was assessed using GC-RMA and a two-way Model I ANOVA. Single enrichment ontological analysis and gene network construction were performed to guide inferences about biological context. Results: In total, across 50 microarrays, ~270 million measurements were obtained. Based on comparisons to known ovarian cancer properties as established in molecular genetics literature, the initial analysis presented emphasizes data quality. Major trends between sample classes included: apical surface and tight junction activity, mitotic activity, benign tumor suppression, epithelial-mesenchymal transitioning, tumor oncogene activity, and paracrine signaling. A list of differentially expressed transcripts has been produced to enable rapid comparisons with published biomarker lists, but it is expected that detailed alternative transcript analysis will refine these predictions. Conclusions: A data set of 50 arrays, from carefully dissected serous ovarian surface epithelial-stromal tumors, has been produced, from which high quality measurements were obtained. While relatively small in number, this represents an important addition to the community pool of ovarian tumor samples, and the chosen platform enables bridging between 3' expression and exome sequencing data sets. This represents a significant contribution to the ovarian cancer genetics community. A total of 50 human ovary samples were used in analysis: 23 tissue samples laser capture microdissected from an ovary with a benign serous tumor (specifically 4 normal epithelium samples, 5 tumor samples, 6 stroma samples adjacent to the tumor, and 8 stroma samples distal of the tumor), and 27 tissue samples laser capture microdissected from an ovary with a malignant serous tumor (specifically 5 normal epithelium samples, 8 tumor samples, 7 stroma samples adjacent to the tumor, and 7 stroma samples distal of the tumor). Additional cel files were provided which, although were used in the quality control of the data set, were not used in the final experimental analysis. 8 replicates are included as cel files (1 from each cohort previously listed). 14 cel files were also included which failed quality control. Although the replicate and failed cel files were not used in the final analysis, they may still be interesting in other research.

Dataset Information

Extensive Three-Dimensional Intratumor Proteomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens

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