Proteomics Profiling Identifies MCM4 as a Prognostic Biomarker for Postoperative Metastasis in Solid Pseudopapillary...

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor with generally indolent behavior, and surgical resection yields a 5-year survival rate >95%. However, 5% to 10% of patients develop metastases, underscoring the need for reliable prognostic biomarkers to identify individuals at a higher metastatic risk and to optimize postoperative management. In this study, we performed data-independent acquisition mass spectrometry based proteomics profiling on resected primary tumors from 59 SPN patients to identify proteins differentially expressed between metastatic and nonmetastatic cases. A candidate protein, MCM4, was further examined for potential pathogenic functions in vitro. An independent multicenter cohort of 255 patients was subsequently analyzed for MCM4 positivity by immunohistochemistry. Prognostic performance for postoperative metastasis was evaluated using Kaplan-Meier analysis, Cox regression, and time-dependent receiver operating characteristic curves, with histopathological invasion defined as neural, vascular, or peripancreatic invasion. MCM4 protein was aberrantly upregulated in tumors from patients who developed metastasis, and functional assays demonstrated a proproliferative role of MCM4. In the validation cohort, MCM4-positive tumors (MCM4 index, >3%) exhibited a higher Ki-67 index (P = .0006). Patients with MCM4-positive tumors had a higher incidence of metastasis (20.6% vs 4.1%; P = .0019) and significantly shorter metastasis-free survival (MFS; log-rank P < .0001). In univariate Cox regression analysis, MCM4 positivity was significantly associated with reduced MFS (hazard ratio, 12.78; 95% CI, 3.01-54.31; P = .0006). In multivariate Cox regression analysis, MCM4 positivity remained an independent prognostic biomarker for shorter postoperative MFS after adjustment for histopathological invasion (hazard ratio, 11.55; 95% CI, 2.76-48.37; P = .0008). Time-dependent receiver operating characteristic analyses demonstrated that MCM4 positivity achieved area under the curves of 0.817 (95% CI, 0.763-0.864) at 3 years and 0.777 (95% CI, 0.720-0.828) at 5 years for postoperative metastasis assessment. Taken together, these findings identify MCM4 positivity as an independent prognostic biomarker for postoperative metastasis risk assessment in SPN.