Tan Ming, Schaffalitzky de Muckadell Ove B, Jøergensen Maiken Thyregod
Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark.
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
J Pancreat Cancer. 2020 Aug 5;6(1):73-84. doi: 10.1089/pancan.2020.0007. eCollection 2020.
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. 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. 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 ( < 5e-05) and four downregulated ( < 6e-04) gene modules in FPC compared to SPC. Among the DEG modules, the upregulated modules include 14 significant genes ( < 1e-06): , , , , , , , , , , , , , and . The downregulated modules include 170 genes ( < 1e-06), among them 13 highly significant genes ( < 1e-10): , , , , , , , , , , , , and . 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, , , and were found as highly connective hub genes associated with both FPC and SPC. 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.
高级别胰腺上皮内瘤变（PanIN）是侵袭性癌前病变，与进展为胰腺导管腺癌（PDAC）的风险相关。描绘高级别家族性胰腺癌（FPC）相关PanIN病变中共同失调的基因活性，可能有助于明确从家族性PanIN进展为PDAC过程中的分子事件。我们进行了加权基因共表达网络分析（WGCNA），以识别与FPC相关PanIN病变相关的共表达基因簇，这些样本包括13例来自FPC易感个体的PanIN-2/3样本、6例来自散发性胰腺癌（SPC）患者的PDAC样本以及4例正常供体胰腺组织样本。WGCNA识别出七个差异表达基因（DEG）模块和两个共同表达基因（CEG）模块，这些模块在FPC和SPC中对基因本体论（GO）术语有显著富集，与SPC相比，FPC中有三个上调（<5e-05）和四个下调（<6e-04）基因模块。在DEG模块中，上调模块包括14个显著基因（<1e-06）： ， ， ， ， ， ， ， ， ， ， ， ， ， ， 和 。下调模块包括170个基因（<1e-06），其中13个高度显著基因（<1e-10）： ， ， ， ， ， ， ， ， ， ， ， ， 和 。DEG模块在与线粒体结构和三磷酸腺苷代谢过程、细胞外结构和结合特性、体液和补体介导的免疫反应、配体门控离子通道活性以及跨膜受体活性相关的GO术语中富集。在CEG模块中， ， ， 和 被发现是与FPC和SPC都相关的高度连接的枢纽基因。如基因网络活性和共同表达的高连接性枢纽基因所示，FPC相关的PanIN病变与SPC表现出共同的分子基础。FPC和SPC的不同分子病理学涉及多个共表达基因簇，这些基因簇在包括细胞外活动和线粒体功能在内的GO术语中富集。
