Abstract
In previous studies by the authors, aurora kinase A (AURKA) was demonstrated as an independent poor prognostic marker for the recurrence of localized gastrointestinal stromal tumors (GISTs) and for the progression of advanced GISTs. In the present study, the prognostic effect of genes involved in cell cycle regulation in GISTs was further examined. Leading edge analysis in gene set enrichment analysis was used to identify the most common genes in the top 10 enriched gene sets of high-risk patients with GISTs in a Japanese study. The obtained gene list was uploaded to the Pathway Interaction Database to search for critical pathways. Selected genes within the pathway were subsequently verified through immunohistochemistry (IHC) in another cohort of patients. A total of 5 genes in 'PLK1 signaling events,' namely AURKA, polo-like kinase 1 (PLK1), cell division cycle 25C (CDC25C), budding uninhibited by benzimidazoles (BUB1), and targeting protein for Xklp2 (TPX2), were identified for subsequent study. Among the Japanese cohort, all 5 genes, except BUB1, were significant prognostic factors for poor recurrence-free survival (RFS). Among 141 patients enrolled for the IHC study, all 5 genes exhibited variable expression patterns. In the association study, only AURKA exhibited significant overexpression in non-gastric tumors. Although all 5 genes were considered as risk factors for poor RFS based on a univariate analysis, only the mitotic count and expression levels of CDC25C, BUB1, and TPX2 retained prognostic effects in the multivariate analysis. The PLK1 signaling pathway is crucial in the disease progression of GISTs. Genes within this pathway may serve as predictive markers for adjuvant therapy.