Uncoupling of MT1E transcription and translation in high-CNA colorectal cancer: A proteostatic adaptation as driver of aggressiveness.

Abstract

e15577 Background: Somatic copy number alterations (CNAs) drive chromosomal instability in colorectal cancer (CRC). We aimed to determine the prognostic value of CNA burden and elucidate its underlying molecular adaptations, focusing on the discovered RNA-protein decoupling of metallothionein (MT1E). Methods: Genome-wide CNA burden was analyzed in 78 CRC patients (Taipei Veterans General Hospital) via targeted NGS and validated in 437 patients (TCGA-COAD). Multi-omic integration screened for critical dysregulated targets in high-CNA tumors. Findings were validated by examining MT1E protein expression using immunohistochemistry and digital pathology in an independent cohort (n = 189). Results: High CNA burden was mutually exclusive with MSI-high status and consistently predicted inferior overall survival in both cohorts (TVGH: HR = 1.80, p = 0.019; TCGA: HR = 1.71, p = 0.009). Notably, integrative analysis revealed a striking discordance regarding MT1E: while high-CNA tumors exhibited significant downregulation of MT1E mRNA (logFC = −1.13; FDR = 4.23×10⁻¹²), protein-level analysis demonstrated that high MT1E protein expression was paradoxically associated with aggressive disease and worse survival (p = 0.028). This suggests that post-transcriptional stabilization of MT1E acts as a critical stress-adaptive mechanism specific to genomically unstable tumors. Conclusions: High CNA burden serves as a robust prognostic biomarker in CRC, identifying a high-risk subgroup characterized by stress-adaptive MT1E protein stabilization despite transcriptional repression. These findings expose a potential proteostatic vulnerability in chromosomal-unstable CRC that could be exploited therapeutically.