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Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer

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...

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Autores principales: Tan, Ming, Schaffalitzky de Muckadell, Ove B., Jøergensen, Maiken Thyregod
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc., publishers 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415888/
https://www.ncbi.nlm.nih.gov/pubmed/32783019
http://dx.doi.org/10.1089/pancan.2020.0007
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author Tan, Ming
Schaffalitzky de Muckadell, Ove B.
Jøergensen, Maiken Thyregod
author_facet Tan, Ming
Schaffalitzky de Muckadell, Ove B.
Jøergensen, Maiken Thyregod
author_sort Tan, Ming
collection PubMed
description 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.
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spelling pubmed-74158882020-08-10 Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer Tan, Ming Schaffalitzky de Muckadell, Ove B. Jøergensen, Maiken Thyregod J Pancreat Cancer Original Article 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. Mary Ann Liebert, Inc., publishers 2020-08-05 /pmc/articles/PMC7415888/ /pubmed/32783019 http://dx.doi.org/10.1089/pancan.2020.0007 Text en © Ming Tan et al., 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Tan, Ming
Schaffalitzky de Muckadell, Ove B.
Jøergensen, Maiken Thyregod
Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer
title Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer
title_full Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer
title_fullStr Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer
title_full_unstemmed Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer
title_short Gene Expression Network Analysis of Precursor Lesions in Familial Pancreatic Cancer
title_sort gene expression network analysis of precursor lesions in familial pancreatic cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415888/
https://www.ncbi.nlm.nih.gov/pubmed/32783019
http://dx.doi.org/10.1089/pancan.2020.0007
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