Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers.

Abstract

Proteomic signatures associated with clinical measures of more aggressive cancers could yield molecular clues as to disease drivers. Here, utilizing the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets, we defined differentially expressed proteins and mRNAs associated with higher grade or higher stage, for each of seven cancer types (breast, colon, lung adenocarcinoma, clear cell renal, ovarian, uterine, and pediatric glioma), representing 794 patients. Widespread differential patterns of total proteins and phosphoproteins involved some common patterns shared between different cancer types. More proteins were associated with higher grade than higher stage. Most proteomic signatures predicted patient survival in independent transcriptomic datasets. The proteomic grade signatures, in particular, involved DNA copy number alterations. Pathways of interest were enriched within the grade-associated proteins across multiple cancer types, including pathways of altered metabolism, Warburg-like effects, and translation factors. Proteomic grade correlations identified protein kinases having functional impact in vitro in uterine endometrial cancer cells, including MAP3K2, MASTL, and TTK. The protein-level grade and stage associations for all proteins profiled—along with corresponding information on phosphorylation, pathways, mRNA expression, and copy alterations—represent a resource for identifying new potential targets. Proteomic analyses are often concordant with corresponding transcriptomic analyses, but with notable exceptions.