Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer
Ming Tan, Ove B. Schaffalitzky de Muckadell, Maiken Thyregod Jøergensen
Abstract
Purpose: High-grade pancreatic intraepithelial neoplasia (PanIN) are aggressive premalignant lesions, associated with risk of progression to pancreatic ductal adenocarcinoma (PDAC). A depiction of co-dysregulated gene activity in high-grade familial pancreatic cancer (FPC)-related PanIN lesions may characterize the molecular events during the progression from familial PanIN to PDAC. Materials and Methods: We performed weighted gene coexpression network analysis (WGCNA) to identify clusters of coexpressed genes associated with FPC-related PanIN lesions in 13 samples with PanIN-2/3 from FPC predisposed individuals, 6 samples with PDAC from sporadic pancreatic cancer (SPC) patients, and 4 samples of normal donor pancreatic tissue. Results: WGCNA identified seven differentially expressed gene (DEG) modules and two commonly expressed gene (CEG) modules with significant enrichment for Gene Ontology (GO) terms in FPC and SPC, including three upregulated ( p < 5e-05) and four downregulated ( p < 6e-04) gene modules in FPC compared to SPC. Among the DEG modules, the upregulated modules include 14 significant genes ( p < 1e-06): ALOX12-AS1 , BCL2L11 , EHD4 , C4B , BTN3A3 , NDUFA11 , RBM4B , MYOC , ZBTB47 , TTTY15 , NAPRT , LOC102606465 , LOC100505711 , and PTK2 . The downregulated modules include 170 genes ( p < 1e-06), among them 13 highly significant genes ( p < 1e-10): COL10A1 , SAMD9 , PLPP4 , COMP , POSTN , IGHV4–31 , THBS2 , MMP9 , FNDC1 , HOPX , TMEM200A , INHBA , and SULF1 . The DEG modules are enriched for GO terms related to mitochondrial structure and adenosine triphosphate metabolic processes, extracellular structure and binding properties, humoral and complement mediated immune response, ligand-gated ion channel activity, and transmembrane receptor activity. Among the CEG modules, IL22RA1 , DPEP1 , and BCAT1 were found as highly connective hub genes associated with both FPC and SPC. Conclusion: FPC-related PanIN lesions exhibit a common molecular basis with SPC as shown by gene network activities and commonly expressed high-connectivity hub genes. The differential molecular pathology of FPC and SPC involves multiple coexpressed gene clusters enriched for GO terms including extracellular activities and mitochondrion function.