Proteotranscriptomic Analyses of Microsatellite-Stable Early-Onset Colorectal Cancer

PURPOSE The prevalence and death rates of early-onset colorectal cancer (EOCRC) have been increasing at an alarming rate since 1994. Compared with late-onset colorectal cancer (LOCRC), EOCRC is more aggressive and resistant to treatment. Despite KRAS mutations and the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway's significant role in colorectal cancer tumorigenesis and progression, these mutations are less frequent in patients with EOCRC. METHODS In this study, we conducted proteotranscriptomic profiling of two independent cohorts (MD Anderson for testing and The Cancer Genome Atlas for validation), comparing EOCRC and LOCRC tumors. Our focus was on sporadic, microsatellite-stable, treatment-naïve patients with early-onset (60 years) colorectal adenocarcinomas. RESULTS Our analysis revealed consistent molecular differences between EOCRC and LOCRC, particularly in pathway enrichment profiles. The two pathways with the highest levels of significant gene set enrichment analysis in EOCRC tumors were the downregulation of epithelial-mesenchymal transition and upregulation of Wnt/β-catenin signaling pathways. Both testing and validation cohorts showed a consistent enrichment in hallmark KRAS signaling. However, using the novel KRAS-ERK gene signatures to better capture the pathway signaling functionality, we identified a consistent upregulation of MAPK signaling specifically in EOCRC tumors. Further analysis of this enrichment in wild-type RAS GTPase ( KRAS , NRAS , and HRAS ) tumors confirmed significant MAPK upregulation in EOCRC wild-type RAS tumors ( P < .001). Proteomic analysis further supported these transcriptomic findings, reinforcing the molecular distinctions in EOCRC. CONCLUSION This study not only elucidates the unique molecular attributes of EOCRC but also lays the groundwork for exploring MAPK-targeted therapies specifically for this age group. Given the increasing prevalence of EOCRC, our findings highlight the need for larger investigations into MAPK upregulation in EOCRC and its potential as a target for precision therapies.