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Porcine familial adenomatous polyposis model enables systematic analysis of early events in adenoma progression.

ABSTRACT: We compared gene expression in low and high-grade intraepithelial dysplastic polyps from pigs carrying an APC ¹³¹¹ truncating mutation orthologous to human APC ¹³⁰⁹ , analysing whole samples and microdissected dysplastic epithelium. Gene set enrichment analysis revealed differential expression of gene sets similar to human normal mucosa versus T1 stage polyps. Transcriptome analysis of whole samples revealed many differentially-expressed genes reflecting immune infiltration. Analysis of microdissected dysplastic epithelium was markedly different and showed increased expression in high-grade intraepithelial neoplasia of several genes known to be involved in human CRC; and revealed possible new roles for GBP6 and PLXND1. The pig model thus facilitates analysis of CRC pathogenesis.

SUBMITTER: Flisikowska T

PROVIDER: S-EPMC5529429 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Porcine familial adenomatous polyposis model enables systematic analysis of early events in adenoma progression.

Flisikowska Tatiana T Stachowiak Monika M Xu Hongen H Wagner Alexandra A Hernandez-Caceres Alejandra A Wurmser Christine C Perleberg Carolin C Pausch Hubert H Perkowska Anna A Fischer Konrad K Frishman Dmitrij D Fries Ruedi R Switonski Marek M Kind Alexander A Saur Dieter D Schnieke Angelika A Flisikowski Krzysztof K

Scientific reports 20170726 1

We compared gene expression in low and high-grade intraepithelial dysplastic polyps from pigs carrying an APC <sup>1311</sup> truncating mutation orthologous to human APC <sup>1309</sup> , analysing whole samples and microdissected dysplastic epithelium. Gene set enrichment analysis revealed differential expression of gene sets similar to human normal mucosa versus T1 stage polyps. Transcriptome analysis of whole samples revealed many differentially-expressed genes reflecting immune infiltration ...[more]

PMID: 28747659

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Project description:ObjectivesDuodenal cancer in familial adenomatous polyposis (FAP) arises from adenomas. Differentially expressed genes (DEGs) in the duodenal adenoma-carcinoma pathway have been identified in murine FAP models, but similar data in patients with FAP are limited. Identifying such changes may have significance in understanding duodenal polyposis therapies and identifying cancer biomarkers. We performed a genome-wide transcriptional analysis to describe the duodenal adenoma-carcinoma sequence and determine changes distinguishing patients with FAP with and without duodenal cancer.MethodsTranscriptional profiling was performed with the Affymetrix Human Transcriptome Array 2.0 on duodenal biopsies from 12 FAP patients with duodenal cancer (FAP cases) and 12 FAP patients without cancer (FAP controls). DEGs were compared between cancer-normal, adenoma-normal, and cancer-adenoma in FAP cases and between adenomas from FAP cases and FAP controls. Significant results at P < 0.05 were filtered using fold change > 2.ResultsTwo hundred twenty-four DEGs were identified at an absolute fold change > 2. In adenoma-normal, downregulation of DEGs involved in metabolism of brush border proteins (LCT), lipids (APOB/A4), reactive oxygen species (GSTA2), and retinol (RBP2) was observed. In the cancer-adenoma comparison, upregulation of DEGs involved in cell invasion/migration (POSTN, SPP1) and downregulation of DEGs involved in Paneth differentiation (DEFA5/6) were observed. In the adenoma-adenoma comparison, downregulation of several DEGs (CLCA1, ADH1C, ANXA10) in FAP case adenomas was observed. DEGs with therapeutic potential include SPP1, which is involved in both cyclooxygenase and epidermal growth factor receptor pathways targeted by the sulindac/erlotinib combination for duodenal polyposis.DiscussionWe describe DEGs in the human duodenal adenoma-carcinoma sequence in FAP, which may have prognostic and therapeutic significance. Validation studies are needed to confirm these findings.

Dataset Information

Porcine familial adenomatous polyposis model enables systematic analysis of early events in adenoma progression.

Publications

Porcine familial adenomatous polyposis model enables systematic analysis of early events in adenoma progression.

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