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Identification of an intermediate signature that marks the initial phases of colorectal adenoma-carcinoma transition

ABSTRACT: The colorectal adenoma-carcinoma sequence describes the stepwise progression from normal to dysplastic epithelium and then to carcinoma; only a small proportion of colorectal adenoma (CRA) progresses to colorectal carcinoma (CRC). Presently, endoscopic intervention is used on patients with CRAs of high grade dysplasia, diameters > 1 cm, or villous components > 25% who are at higher risk than other CRA sufferers. During the process, biopsy samples were taken for conventional histological diagnosis, but poor pathomorphological sensitivity and specificity greatly limit the diagnostic accuracy. Unfortunately, there are no reliable molecular criteria available that can predict the potential development of CRA to CRC. In present study, we use microarrays to detail the global programme of gene expression underlying the gradual progress of colorectal adenoma-carcinoma sequence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22242 | GEO | 2010/08/29

SECONDARY ACCESSION(S): PRJNA127727

REPOSITORIES: GEO

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Project description:Background. Most colorectal cancers (CRC) arise in a progression through adenoma to carcinoma phenotypes as a consequence of altered genetic information. Clinical progression of CRC may occur in parallel with distinctive signaling alterations. We designed multidirectional analyses integrating microarray-based data with biostatistics and bioinformatics to elucidate the signaling and metabolic alterations underlying CRC development in the adenoma-carcinoma sequence. Methodology/Principal Findings. Studies were performed on normal mucosa, adenoma, and CRC samples obtained during surgery or colonoscopy. Collections of cryostat sections prepared from the tissue samples were evaluated by a pathologist to control the relative cell type content. RNA was isolated from 105 macro- and 40 microdissected specimens. The measurements were done using Affymetrix GeneChip HG-U133plus2, and probe set data were generated using two normalization algorithms: MAS5 and GCRMA with LVS. The data were evaluated using pair-wise comparisons and data decomposition into SVD modes. The method selected for the functional analysis used the Kolmogorov-Smirnov test. Based on a consensus of the results obtained by two tissue handling procedures, two normalization algorithms, and two probe set sorting criteria, we identified six KEGG signaling and metabolic pathways (cell cycle, DNA replication, p53 signaling pathway, purine metabolism, pyrimidine metabolism, and RNA polymerase) that are significantly altered in both macro- and microdissected tumor samples compared to normal colon. On the other hand, pathways altered between benign and malignant tumors were identified only in the macrodissected tissues. Conclusion/Significance. Multidirectional analyses of microarray data allow the identification of essential signaling alterations underlying CRC development. Although the proposed strategy is computationally complex and labor–intensive, it may reduce the number of false results. Gene expression profiles of 40 tissue samples representing distant full-thickness normal colon, normal colon mucosa dissected from tumor, adenoma, and carcinoma. Gene expression profiles of 105 tissue samples representing colon carcinomas, adenocarcinomas, and normal colon samples.