Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and drug resistant and is one of the most lethal solid malignancies. Genomic profiling studies have defined the molecular subtypes and mutational landscape of PDAC and extensive gene expression profiling dataset have been accumulated to date. However, there is a knowledge gap on the consistency of gene expression across profiled PDAC samples and this limits the prospects of clinical translation. To facilitate novel drug target prioritization and biomarker discovery, we have extensively analyzed over 20 publicly accessible datasets. We report the most consistently expressed genes in PDAC tissues compared to non-tumors. Specifically, we identified 3,938 consistent genes, including 2,010 consistently upregulated genes, topmost of which included LAMC2, TMPRSS4, S100P, SLC6A14, COL10A1, CTSE, LAMB3, CEACAM5/6, and glucose transporter SLC2A1, and 1,928 consistently downregulated genes top among which include AOX1, IAPP, albumin (ALB), SERPINI2, PDK4 and PNLIPRP1/2 (adjusted P<0.05). Over 50% of the genes are unknown. In addition, these genes largely reflected the same expression pattern in bulk and single cell RNA sequencing analysis, showed tumors-specificity, and correlated with several cancer indices including proliferation, metastasis, mutation and tumor grade. Pathway enrichment analyses revealed ‘pathways in cancer', ‘focal adhesion', ‘p53', ‘cell cycle', ‘transcription factor binding', “glycolysis” among upregulated processes. These pathway alterations were accompanied by profound metabolic alterations and signatures of disrupted pancreatic homeostasis. Interactome and disease ontology analyses further linked the consistent genes with precancerous conditions, PDAC, and malignancy. We found that ~41% of the genes predicted patients' overall survival in at least two datasets while clustering analyses and receiver operating characteristic analysis uncovered highly probable biomarkers. Subsequent analysis of gene silencing datasets identified 185 ‘high-priority' genes (notably candidates in cell cycle and glycolysis) whose knockdown suppress PDAC viability. Our multi-dimensional analysis is an important milestone in the quest for mechanisms, drug targets and biomarkers in PDAC, and outlines an adaptable analytical approach that can aid biomarker or therapeutic target discovery in other cancers.
Citation Format: Zeribe Chike Nwosu, Heather C. Giza, Verodia Charlestin, Maya Nassif, Daeho Kim, Samantha Kemp, Nina G. Steele, Costas A. Lyssiotis, Marina Pasca di Magliano. Identification of high priority genes for basic and translational pancreatic cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG02.
