MKI67 Enrichment Characterizes a Proliferative and Genomically Unstable Phenotype in Pancreatic Ductal Adenocarcinoma

Background/Objectives: Ki67 is a well-established histologic proliferation marker across many cancers; however, its clinical application in pancreatic ductal adenocarcinoma (PDAC) has remained limited. Multiple studies have demonstrated that Ki67 is prognostic in PDAC, with higher Ki67 expression associated with worsened outcomes. In this study, we aimed to characterize the underlying biology of Ki67-enriched tumors. Methods: Clinical and transcriptional data from PDAC patients were obtained from The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets. Mutational analysis from the TCGA cohort was also performed. Patients within each study were stratified into low- and high-expression groups based on the median transcript levels. Each dataset was analyzed independently, and differences between groups were subsequently compared across studies. Results: Consistent with their enhanced proliferative capacity, MKI67-high tumors were consistently enriched in pro-proliferative cellular pathways including E2F targets, MYC targets, and mitotic spindle formation as well as pro-growth metabolic pathways across all studies. MKI67-high PDAC is associated with higher histologic grading with similar pathologic staging. High expression was associated with worsened overall and disease-free survival in the TCGA cohort, although this was not consistently observed across external validation datasets. MKI67-high tumors exhibited a significantly higher mutational burden than the MKI67-low tumors. Conclusions: MKI67 enrichment in PDAC correlates with aggressive tumor biology, enhanced proliferative signaling, genomic instability, and distinct microenvironmental and immune features. MKI67-high tumors demonstrate a reproducible association with proliferative signaling, genomic instability, and aggressive biological features across multiple transcriptomic datasets. Further validation is required to determine the clinical utility of MKI67 as a biomarker in PDAC.