CPSF1 Is Co-Amplified with MYC but Is Independently Associated with Alternative Polyadenylation in Cancer

Cleavage and polyadenylation (CPA) is a co-transcriptional mRNA processing mechanism that is central to mRNA and protein function. Dysregulation of CPA is widespread in cancer, promotes oncogenic programs, and affects patient outcomes. The CPA machinery is composed of multiple factors, and while prior research has investigated the impact of CPA gene expression on cancer phenotypes, the contribution of genomic alterations, such as mutations and copy number variations, remains largely unexplored. In this study, we conducted a pan-cancer analysis of genomic alterations in CPA genes. While numerous CPA genes harbor somatic mutations, these mutations do not significantly impact mRNA expression or provide prognostic value. In contrast, we found that copy number alterations in CPA genes have substantial clinical relevance. Notably, we identified the cleavage and polyadenylation specificity factor 1 (<i>CPSF1</i>) gene as the most frequently amplified CPA gene in cancer. While amplification of <i>CPSF1</i> and <i>MYC</i> are co-occuring, <i>CPSF1</i> amplification independently correlates with poor prognosis. We also found that <i>CPSF1</i> amplification can impact 3'UTR length regardless of <i>MYC</i> status. Our study highlights the importance of <i>CPSF1</i> as a promising prognostic factor in cancer and as a therapeutic intervention target to study in the future.