Pancreatic ductal adenocarcinoma (PDAC) is known for its poor prognosis with few long-term survivors. This study aimed to establish a prognostic score using unique transcriptomic profiles of long-term survivors to be used as a patient selection tool for meaningful clinical intervention in PDAC. In TCGA PDAC cohort, 16 genes were significantly upregulated in the long-term survivor tumors. A prognostic score was established using these 16 genes by LASSO Cox regression, and PHKG1, HOXA4, ISL2, DMRT3 and TRA2A gene expressions were included in the score. The prognostic value was confirmed in both testing and validation cohorts. The characteristics of the high score tumor was investigated by bioinformatical approach. The high score tumor was associated with TP53 mutation but not with other commonly enhanced signaling pathways in PDAC. The high score tumor was associated with higher tumor mutational burden and unfavorable tumor microenvironment (TME), such as lower infiltration of CD8-positive T cells and dendritic cells, and less cell composition of mature blood vessels and fibroblasts. The high score tumor was also associated with enhanced cell proliferation and margin positivity after surgery. The impact of score component genes on the cell proliferation was investigated by in vitro experiments. Silencing of the score component genes promoted cell proliferation. In conclusion, the prognostic score predicted PDAC patient survival and was associated with cancer aggressiveness such as unfavorable TME and enhanced cell proliferation.
Keywords: HOX; Pancreatic ductal adenocarcinoma; long-term survivor; score; survival cancer; transcriptome.
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