miRNA expression in colon polyps provides evidence for a multihit model of colon cancer

• Published in: PloS one Vol. 6; no. 6; p. e20465
• Main Authors: Oberg, Ann L, French, Amy J, Sarver, Aaron L, Subramanian, Subbaya, Morlan, Bruce W, Riska, Shaun M, Borralho, Pedro M, Cunningham, Julie M, Boardman, Lisa A, Wang, Liang, Smyrk, Thomas C, Asmann, Yan, Steer, Clifford J, Thibodeau, Stephen N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.06.2011; Public Library of Science (PLoS)
• Subjects: Accounting; Adenoma; Adenoma - genetics; Analysis; Biology; Brain cancer; Cancer; Cancer genetics; Cell adhesion & migration; Chromosomes, Human, Pair 14 - genetics; Cluster Analysis; Colon; Colon - metabolism; Colon - pathology; Colon cancer; Colonic Neoplasms - genetics; Colonic Polyps - genetics; Colorectal cancer; Deactivation; Defects; Deoxyribonucleic acid; DNA; DNA repair; Epigenetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomes; Health sciences; Humans; Inactivation; Laboratories; Medicine; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Mismatch repair; MLH1 protein; Models, Biological; Mucosa; Ovarian cancer; Pathology; Physics; Polyps; Principal Component Analysis; Repair; Statistical analysis; Statistical methods; Stem cells; Subgroups; Transcription factors; Transformation; Tumors; United States > US; Minnesota
• DOI: 10.1371/journal.pone.0020465
• ISSN: 1932-6203

Changes in miRNA expression are a common feature in colon cancer. Those changes occurring in the transition from normal to adenoma and from adenoma to carcinoma, however, have not been well defined. Additionally, miRNA changes among tumor subgroups of colon cancer have also not been adequately evaluated. In this study, we examined the global miRNA expression in 315 samples that included 52 normal colonic mucosa, 41 tubulovillous adenomas, 158 adenocarcinomas with proficient DNA mismatch repair (pMMR) selected for stage and age of onset, and 64 adenocarcinomas with defective DNA mismatch repair (dMMR) selected for sporadic (n = 53) and inherited colon cancer (n = 11). Sporadic dMMR tumors all had MLH1 inactivation due to promoter hypermethylation. Unsupervised PCA and cluster analysis demonstrated that normal colon tissue, adenomas, pMMR carcinomas and dMMR carcinomas were all clearly discernable. The majority of miRNAs that were differentially expressed between normal and polyp were also differentially expressed with a similar magnitude in the comparison of normal to both the pMMR and dMMR tumor groups, suggesting a stepwise progression for transformation from normal colon to carcinoma. Among the miRNAs demonstrating the largest fold up- or down-regulated changes (≥4), four novel (miR-31, miR-1, miR-9 and miR-99a) and two previously reported (miR-137 and miR-135b) miRNAs were identified in the normal/adenoma comparison. All but one of these (miR-99a) demonstrated similar expression differences in the two normal/carcinoma comparisons, suggesting that these early tumor changes are important in both the pMMR- and dMMR-derived cancers. The comparison between pMMR and dMMR tumors identified four miRNAs (miR-31, miR-552, miR-592 and miR-224) with statistically significant expression differences (≥2-fold change).