Unknown,Transcriptomics,Genomics,Proteomics

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Comparison of Cancer-Associated Genetic Abnormalities in Columnar-Lined Esophagus with and without Goblet Cells

ABSTRACT: The requirement of goblet cells (intestinal metaplasia; IM) to define BarrettM-bM-^@M-^Ys esophagus (BE) remains controversial as some studies have shown that the risk of progression to esophageal adenocarcinoma (EAC) is similar for non-goblet cell metaplasia (NGM) and IM. IM harbors genomic aberrations in known cancer-associated genes and these have been linked to increased EAC risk. No detailed studies have explored DNA alterations in NGM. We hypothesized that a comparison of DNA alterations in cancer-associated genes in IM and NGM samples would provide insight into their relative risks for progression to EAC. Patient biopsies were analyzed using Affymetrix SNP 6.0 arrays, FISH, and targeted resequencing of 20 frequently mutated EAC genes. Frequent CNAM-bM-^@M-^Ys targeting cancer-associated genes were found in IM whereas no such changes were observed in NGM. In one subject, FISH confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy. Targeted sequencing in a subset of metaplasia tissues revealed 11 non-synonymous mutations in 16 IM samples and 2 mutations in 19 NGM samples. Our results show that IM has a much higher frequency of cancer-associated mutations than NGM and is therefore likely to pose a higher risk for development of EAC. 57 non-goblet metaplasia, intestinal metaplasias, and composite specimens from 45 subjects were studied. DNA copy number abnormalities (CNAM-bM-^@M-^Ys) were identified using Affymetrix arrays and fluorescence in situ hybridization (FISH). Data was processed in Nexus 6.0 (BioDiscovery, CA). Targeted sequencing of all exons from twenty genes found to be frequently mutated in EAC was performed on metaplasia samples using Ion AmpliSeqM-bM-^DM-" DNA sequencing.

ORGANISM(S): Homo sapiens

SUBMITTER: Santhoshi Bandla

PROVIDER: E-GEOD-40769 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Intestinal metaplasia (IM) is a gastric precancerous lesion that precedes the development of gastric cancer in up to 3.77 cases/1000 person-years. It consists in a trans-differentiation process of gastric to intestinal tissue. Two histological subtypes exist, complete (CIM) and incomplete (IIM), the latter having higher progression rates to gastric cancer . Our objective was to identify molecular processes responsible for the tumoral transition from intestinal metaplasia to GC and the initial steps of this lesion Methods: We used expression microarray to compare the transcriptome of intestinal metaplasia subtypes that progress to gastric cancer (IIM-GC and CIM-GC) after a follow-up period with respect to those that do not progress (IIM control and CIM control). Also, IM-NoGC (IM control, comprising both IIM and CIM Control) was compared with healthy gastric mucosa. Differentially expressed genes were obtained and functional analyses (GSEA and IPA softwares) were performed. Some deregulated genes were validated by qPCR. Results: Histological subtypes of intestinal metaplasia that progress or not to GC differ less among them than to healthy mucosa. Incomplete intestinal metaplasia has a higher number of over-expressed carcinogenic genes and molecular processes than the complete subtype. Most relevant molecular processes and genes in this group include antigenic processing, inflammation, activation of cell cycle and cell proliferation, oncogenes and tumor suppressors. When IM-NoGC is compared with healthy gastric mucosa new identified transcripts include TRIM, TMEM, homeobox, transporters and nucleolar RNAs SNORDs116. We confirm previously reported processes such us intestinal differentiation, metabolism of lipids and of xenobiotics and identify new ones such as non tumoral Warburg effect and melatonin degradation. Conclusions: Differentially expressed genes and molecular processes have been identified for the first time in intestinal metaplasia that progress to gastric cancer. New genes and molecular processes have also been identified in intestinal metaplasia in comparison with healthy gastric mucosa.

Project description:Barrett's esophagus is characterized by the replacement of squamous epithelium with specialized intestinal metaplastic mucosa. The exact mechanisms of initiation and development of Barrett's metaplasia remain unknown, but a hypothesis of successful adaptation against noxious reflux components has been proposed. To search for the repertoire of adaptation mechanisms of Barrett's metaplasia, we employed high-throughput functional genomic and proteomic methods that defined the molecular background of metaplastic mucosa resistance to reflux. Transcriptional profiling was established for 23 pairs of esophageal squamous epithelium and Barrett's metaplasia tissue samples using Affymetrix U133A 2.0 GeneChips and validated by quantitative real-time polymerase chain reaction. Differences in protein composition were assessed by electrophoretic and mass-spectrometry-based methods. Among 2,822 genes differentially expressed between Barrett's metaplasia and squamous epithelium, we observed significantly overexpressed metaplastic mucosa genes that encode cytokines and growth factors, constituents of extracellular matrix, basement membrane and tight junctions, and proteins involved in prostaglandin and phosphoinositol metabolism, nitric oxide production, and bioenergetics. Their expression likely reflects defense and repair responses of metaplastic mucosa, whereas overexpression of genes encoding heat shock proteins and several protein kinases in squamous epithelium may reflect lower resistance of normal esophageal epithelium than Barrett's metaplasia to reflux components. Despite the methodological and interpretative difficulties in data analyses discussed in this paper, our studies confirm that Barrett's metaplasia may be regarded as a specific microevolution allowing for accumulation of mucosal morphological and physiological changes that better protect against reflux injury. Department of Gastroenterology, Medical Center for Postgraduate Education and Maria SkM-EM-^Bodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland 2 types of tissue sample derived from the same patient: > Normal squamous epithelium (NE) from patients with longsegment of BarretM-bM-^@M-^Ys epithelium > Metaplastic epithelium from BarrettM-bM-^@M-^Ys esophagus (BE)

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Comparison of Cancer-Associated Genetic Abnormalities in Columnar-Lined Esophagus with and without Goblet Cells

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