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Gene Expression Changes Associated with the Progression of Intraductal Papillary Mucinous Neoplasms

ABSTRACT: Purpose: The diagnosis of high grade intraductal papillary mucinous neoplasm (IPMN) is difficult to distinguish from low grade IPMN. The aim of this study was to identify potential markers for the discrimination of high grade and invasive IPMN from low and moderate grade IPMN. Experimental Design: Laser capture microdissection was used to isolate distinct foci of low grade, moderate grade, high grade, and invasive IPMN from paraffin embedded archival tissue from 14 patients who underwent resection for IPMN. Most samples included multiple grades in the same specimen. Affymetrix Human Exon microarrays were used for gene expression analysis to compare low and moderate grade (LMD) IPMN to high grade and invasive (HgInv) IPMN. Results: When comparing samples of LMD dysplasia (n=15) to those demonstrating HgInv (n=13), 62 genes were identified as showing significant changes in expression (p≤0.05 and a 2-fold cutoff), with up-regulation of 41 in HgInv IPMN and down-regulation in 21. Changes in gene expression are associated with biological processes related to malignant behavior including cell motion, cell proliferation, response to hypoxia, and epithelial to mesenchymal transition. Hierarchical clustering analysis demonstrated the ability of these 62 differentially expressed genes to distinguish between LMD and HgInv samples. In addition, altered signaling in several TGFβ-related pathways was exhibited in the progression of IPMN to malignancy. Conclusions: This study identifies a set genes associated with the progression of IPMN to malignancy. These genes are potential markers that could be used to identify IPMN requiring surgical resection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26647 | GEO | 2011/12/01

SECONDARY ACCESSION(S): PRJNA136379

REPOSITORIES: GEO

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Project description:Purpose: The diagnosis of high grade intraductal papillary mucinous neoplasm (IPMN) is difficult to distinguish from low grade IPMN. The aim of this study was to identify potential markers for the discrimination of high grade and invasive IPMN from low and moderate grade IPMN. Experimental Design: Laser capture microdissection was used to isolate distinct foci of low grade, moderate grade, high grade, and invasive IPMN from paraffin embedded archival tissue from 14 patients who underwent resection for IPMN. Most samples included multiple grades in the same specimen. Affymetrix Human Exon microarrays were used for gene expression analysis to compare low and moderate grade (LMD) IPMN to high grade and invasive (HgInv) IPMN. Results: When comparing samples of LMD dysplasia (n=15) to those demonstrating HgInv (n=13), 62 genes were identified as showing significant changes in expression (p≤0.05 and a 2-fold cutoff), with up-regulation of 41 in HgInv IPMN and down-regulation in 21. Changes in gene expression are associated with biological processes related to malignant behavior including cell motion, cell proliferation, response to hypoxia, and epithelial to mesenchymal transition. Hierarchical clustering analysis demonstrated the ability of these 62 differentially expressed genes to distinguish between LMD and HgInv samples. In addition, altered signaling in several TGFβ-related pathways was exhibited in the progression of IPMN to malignancy. Conclusions: This study identifies a set genes associated with the progression of IPMN to malignancy. These genes are potential markers that could be used to identify IPMN requiring surgical resection. Using laser capture microdissection, distinct foci of low (n=10), moderate (n=5), and high grade dysplasia (n=6) as well as invasive carcinoma (n=7) were isolated from paraffin embedded archival tissue of 14 patients who underwent resection for IPMN. Gene expression data from Affymetrix Human Exon 1.0ST microarrays was utilized to compare low and moderate grade IPMN to high and invasive IPMN.

Project description:Following parenchymal loss, the liver regenerates restoring normal mass and metabolic function. Prevailing theories on triggering events leading to regeneration include humoral, metabolic and flow-mediated mechanisms, the latter emphasizing the importance of shear stress mediated nitric oxide (NO) regulation. We aimed to investigate whether the grade of resection and hence the portal venous pressure and sinusoidal shear stress increase, would be reflected in the gene expression profiles in the liver remnant by employing a global porcine cDNA microarray chip with approximately 23 000 genes represented. Six pig livers were resected with 62% (Low Portal Pressure Resection, LPPR) and 75% (High Portal Pressure Resection) resulting in a portal venous pressure increase from a baseline of 6.1 mmHg to 8.2 and 12 mmHg respectively. By sampling consecutive biopsies from the liver remnants we found differentially expressed genes in the HPPR group to have functions related primarily to apoptosis, nitric oxide metabolism and oxidative stress, whereas differentially expressed genes in the LPPR group potentially regulate the cell cycle. Common to both groups was the upregulation of genes regulating inflammation, transport, cell proliferation and development and protein metabolism. Also common to both groups was both up- and downregulation of genes regulating cell-cell signaling, signal transduction, cell adhesion and translation. Genes regulating the metabolism of lipids, hormones, amines, and alcohol were downregulated in both groups. Conclusions: The genetic regenerative response in the liver remnant to varies according to the level of resection. Keywords: time course, treatment comparison Three pigs underwent a 62% liver resection (low-pressure resection, LPR) and three underwent a 75% resection (high-pressure resection, HPR). Biopsies from the liver remnant were taken from all animals at time points 1, 30, 90, minutes and 3, 4 and 6 hours after resection. Expression profiling was conducted by hybridising each sample against a common reference, consisting of liver RNA from an unrelated animal.

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Gene Expression Changes Associated with the Progression of Intraductal Papillary Mucinous Neoplasms

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