Integrative Omics Analysis Reveals Post-Transcriptionally Enhanced Protective Host Response in Colorectal Cancers with Microsatellite Instability

Abstract

Microsatellite instability (MSI) is a frequent and clinically relevant molecular phenotype in colorectal cancer. MSI cancers have favorable survival compared with microsatellite stable cancers (MSS), possibly due to the pronounced tumor-infiltrating lymphocytes observed in MSI cancers. Consistent with the strong immune response that MSI cancers trigger in the host, previous transcriptome expression studies have identified mRNA signatures characteristic of immune response in MSI cancers. However, proteomics features of MSI cancers and the extent to which the mRNA signatures are reflected at the protein level remain largely unknown. Here, we performed a comprehensive comparison of global proteomics profiles between MSI and MSS colorectal cancers in The Cancer Genome Atlas (TCGA) cohort. We found that protein signatures of MSI are also associated with increased immunogenicity. To reliably quantify post-transcription regulation in MSI cancers, we developed a resampling-based regression method by integrative modeling of transcriptomics and proteomics data sets. Compared with the popular simple method, which detects post-transcriptional regulation by either identifying genes differentially expressed at the mRNA level but not at the protein level or vice versa, our method provided a quantitative, more sensitive, and accurate way to identify genes subject to differential post-transcriptional regulation. With this method, we demonstrated that post-transcriptional regulation, coordinating protein expression with key players, initiates de novo and enhances protective host response in MSI cancers.

Controlling for cellular heterogeneity using single-cell deconvolution of gene expression reveals novel markers of colorectal tumors exhibiting microsatellite instability

“…This is in line with clinical practice, where MSI-L tumors are often considered to be similar to MSS tumors [12]. This grouping has also been used in other studies [13].…”

Quantitative Proteomics of the Cancer Cell Line Encyclopedia

“…MSI is by far the dominant form of hypermutation in the CCLE. Although the proteome of MSI colorectal cancer has been analyzed recently in a panel of ten cell lines and in the TCGA tumor data (Halvey et al, 2013;Liu and Zhang, 2016;Zhang et al, 2014), the CCLE contained MSI samples of multiple tissue lineages. The mRNA data had over a thousand significantly up-and downregulated genes associated with MSI (Figure 5A).…”

“…Additionally, these tumors have increased levels of neoantigens making them attractive for immuneoncology therapies (Baretti and Le, 2018). MSI is the dominant form of hypermutation present in the CCLE, and although the MSI proteome has been studied in colorectal cell lines and tumors (Halvey et al, 2013;Liu and Zhang, 2016), it has not been explored across tissue lineages.…”

Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities

“…Similarly, many of the miRNA and phosphosite markers identified in the supervised analysis (Table S7) have known relationships with the subtype-specific features. Examples include decreased expression of miR-552, miR-592, and miR-181d in the MSI subtype (Liu and Zhang, 2016), decreased expression of the miR-200 family in the Mesenchymal subtype (Korpal et al, 2008), and increased phosphorylation of STAT1 and STAT3 in the MSI and Mesenchymal subtypes, respectively (Pensa et al, 2009). Notably, we found higher copy-number gain of RB1 in the CIN subtype compared to the other subtypes (Figure S6H).…”