Abstract
Inter-tumor heterogeneity is a result of genomic, transcriptional, translational, and post-translational molecular features. To investigate the roles of protein glycosylation in the heterogeneity of high-grade serous ovarian carcinoma (HGSC), we perform mass spectrometry-based glycoproteomic characterization of 119 TCGA HGSC tissues. Cluster analysis of intact glycoproteomic profiles delineates 3 major tumor clusters and 5 groups of intact glycopeptides. It also shows a strong relationship between N-glycan structures and tumor molecular subtypes, one example of which being the association of fucosylation with mesenchymal subtype. Further survival analysis reveals that intact glycopeptide signatures of mesenchymal subtype are associated with a poor clinical outcome of HGSC. In addition, we study the expression of mRNAs, proteins, glycosites, and intact glycopeptides, as well as the expression levels of glycosylation enzymes involved in glycoprotein biosynthesis pathways in each tumor. The results show that glycoprotein levels are mainly controlled by the expression of their individual proteins, and, furthermore, that the glycoprotein-modifying glycans correspond to the protein levels of glycosylation enzymes. The variation in glycan types further shows coordination to the tumor heterogeneity. Deeper understanding of the glycosylation process and glycosylation production in different subtypes of HGSC may provide important clues for precision medicine and tumor-targeted therapy.
Highlights
Inter-tumor heterogeneity is a result of genomic, transcriptional, translational, and posttranslational molecular features
The iTRAQlabeled peptides were split into three aliquots for global proteomic analysis and the parallel enrichments of glycopeptides for glycosite-containing peptides from solid-phase extraction of glycosite-containing peptides (SPEG) and intact glycopeptides (IGPs)[28,30]
Since aberrant glycosylation has been associated with oncongenesis, and is independent of DNA/mRNA gene expression profiles, we examined the degree of glycosylation aberration in high-grade serous ovarian carcinoma (HGSC) by assessing the disconcordance of glycosites and total glycoprotein expression patterns
Summary
Inter-tumor heterogeneity is a result of genomic, transcriptional, translational, and posttranslational molecular features. Solid-phase extraction of glycosite-containing peptides (SPEG) for glycosite analysis[28], and intact glycopeptides for investigation of glycosite-specific glycans (IGPs)[29,30], we profile the N-linked glycoproteome in HGSCs, identifying and quantifying glycosites and their attached glycan structures. We leveraged the expression data of SPEGs and IGPs to cluster the 119 HGSC samples.
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