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Proteome-transcriptome alignment of molecular portraits achieved by self-contained gene set analysis: Consensus colon cancer subtypes case study.

ABSTRACT: Gene set analysis (GSA) has become the common methodology for analyzing transcriptomics data. However, self-contained GSA techniques are rarely, if ever, used for proteomics data analysis. Here we present a self-contained proteome level GSA of four consensus molecular subtypes (CMSs) previously established by transcriptome dissection of colon carcinoma specimens. Despite notable difference in structure of proteomics and transcriptomics data, many pathway-wide characteristic features of CMSs found at the mRNA level were reproduced at the protein level. In particular, CMS1 features show heavy involvement of immune system as well as the pathways related to mismatch repair, DNA replication and functioning of proteasome, while CMS4 tumors upregulate complement pathway and proteins participating in epithelial-to-mesenchymal transition (EMT). In addition, protein level GSA yielded a set of novel observations visible at the proteome, but not at the transcriptome level, including possible involvement of major histocompatibility complex II (MHC-II) antigens in the known immunogenicity of CMS1 and a connection between cholesterol trafficking and the regulation of Integrin-linked kinase (ILK) in CMS3. Overall, this study proves utility of self-contained GSA approaches as a critical tool for analyzing proteomics data in general and dissecting protein-level molecular portraits of human tumors in particular.

SUBMITTER: Glazko G

PROVIDER: S-EPMC6705791 | biostudies-other | 2019

REPOSITORIES: biostudies-other

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Proteome-transcriptome alignment of molecular portraits achieved by self-contained gene set analysis: Consensus colon cancer subtypes case study.

Glazko Galina G Zybailov Boris B Emmert-Streib Frank F Baranova Ancha A Rahmatallah Yasir Y

PloS one 20190822 8

Gene set analysis (GSA) has become the common methodology for analyzing transcriptomics data. However, self-contained GSA techniques are rarely, if ever, used for proteomics data analysis. Here we present a self-contained proteome level GSA of four consensus molecular subtypes (CMSs) previously established by transcriptome dissection of colon carcinoma specimens. Despite notable difference in structure of proteomics and transcriptomics data, many pathway-wide characteristic features of CMSs foun ...[more]

PMID: 31437237

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Project description:The Colorectal Cancer Subtyping Consortium established four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (microsatellite-instability [MSI], Immune), CMS2 (Canonical, epithelial), CMS3 (Metabolic), and CMS4 (Mesenchymal). However, in the clinical practice only patients with MSI tumors have experienced a change in the management of their disease. Proteomics has experimented significant technical advances with the implementation of data-independent acquisition (DIA) as the gold-standard for the analysis of large cohort of patients, providing a dynamic framework of the disease and direct information about the effectors of the biological processes. The aim of this study is the characterization of the proteome of colon cancer CMS by DIA–based proteomics and expand the utility of CMS in the clinical practice. CMS were assigned and differences in the protein profiles between CMS were defined and evaluated using a Systems Biology approach. One hundred fifty-eight paraffin samples from colon cancer patients with stage II-III disease treated with adjuvant chemotherapy were analyzed. After applying quality criteria, 1,940 identified and quantified proteins were used for the analyses. CMS1 had an overexpression of proteins related to immune system, specifically neutrophils, phagocytosis and antimicrobial response, and a glycolytic profile. CMS3 had an overexpression of proteins related to metabolic pathways, while CMS2 showed an intermediate protein profile between CMS1-3, but with a characteristic profile regarding translation, adhesion, and mitochondria and metabolism biological processes. Two proteomics subtypes within CMS2 with different protein characteristics and prognosis were identified. CMS4 was the most different group with an overexpression of proteins related to angiogenesis, extracellular matrix, focal adhesion, and complement activation. In conclusion, DIA LC-MS/MS proteomics characterization of CRC CMS established new features for each CMS, such as a higher mitochondrial activity in CMS2 or an overexpression of proteins related to phagocytosis in CMS1, but also confirmed previous findings established using transcriptomics such as an overexpression of proteins related to angiogenesis in CMS4. In this CMS4 subtype, several adhesion-related proteins suggested a high metastatic profile and a possible chemoresistance that may explain the worse prognosis of this subtype. CMS1 was characterized as immune and glycolitic-active subtype, being the combination of immunotherapy and glycolytic inhibitors a possible therapeutic strategy. Additionally, two different CMS2 proteomics-based subtypes with different prognosis and possible therapeutic targets were identified. These proccesses could be used as therapeutic targets in the future.

Dataset Information

Proteome-transcriptome alignment of molecular portraits achieved by self-contained gene set analysis: Consensus colon cancer subtypes case study.

Publications

Proteome-transcriptome alignment of molecular portraits achieved by self-contained gene set analysis: Consensus colon cancer subtypes case study.

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