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

Oberg AL, French AJ, Sarver AL, Subramanian S, Morlan BW, Riska SM, Borralho PM, Cunningham JM, Boardman LA, Wang L, Smyrk TC, Asmann Y, Steer CJ, Thibodeau SN - PLoS ONE (2011)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT
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).

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Plots of principal components from PCA analyses.Horizontal axis corresponds to principal component 1 (PC1), vertical axis corresponds to PC2, and depth axis corresponds to PC3. Points are colored by group status. The percent of variation explained by a particular PC is indicated in the axis label. (A) pMMR1 evaluated by Dukes stage; (B) evaluation by age of onset (pMMR1 - old and pMMR2 - young). (C) evaluation of 2 groupings of dMMR cases (dMMR1 - epigenetic silenced MLH1 and dMMR2 - germline); (D) the pMMR1 groups MSI-L and MSS tumors. Colors for each of the groups being compared are shown in the upper right legend box.
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pone-0020465-g002: Plots of principal components from PCA analyses.Horizontal axis corresponds to principal component 1 (PC1), vertical axis corresponds to PC2, and depth axis corresponds to PC3. Points are colored by group status. The percent of variation explained by a particular PC is indicated in the axis label. (A) pMMR1 evaluated by Dukes stage; (B) evaluation by age of onset (pMMR1 - old and pMMR2 - young). (C) evaluation of 2 groupings of dMMR cases (dMMR1 - epigenetic silenced MLH1 and dMMR2 - germline); (D) the pMMR1 groups MSI-L and MSS tumors. Colors for each of the groups being compared are shown in the upper right legend box.

Mentions: The global miRNA expression patterns were then visually examined in various pre-defined tumor sub-groups to determine if these could be distinguished. The PCA plots for these analyses are shown in Figure 2 (data not shown for the hierarchical cluster analyses). Within the pMMR1 group of tumors, there were no apparent discernible differences based on stage, either across all three stages or between any two stages (Stage A not included due to small numbers), or based on gender. Additionally, no separation of groups was visible between tumors with an older age of onset (≥50 y/o, pMMR1) and those with a younger age of onset (<50 y/o, pMMR2). An analysis of tumors within each of the two dMMR subtypes, dMMR1 (somatic) versus dMMR2 (germline), also showed no discernible differences.


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

Oberg AL, French AJ, Sarver AL, Subramanian S, Morlan BW, Riska SM, Borralho PM, Cunningham JM, Boardman LA, Wang L, Smyrk TC, Asmann Y, Steer CJ, Thibodeau SN - PLoS ONE (2011)

Plots of principal components from PCA analyses.Horizontal axis corresponds to principal component 1 (PC1), vertical axis corresponds to PC2, and depth axis corresponds to PC3. Points are colored by group status. The percent of variation explained by a particular PC is indicated in the axis label. (A) pMMR1 evaluated by Dukes stage; (B) evaluation by age of onset (pMMR1 - old and pMMR2 - young). (C) evaluation of 2 groupings of dMMR cases (dMMR1 - epigenetic silenced MLH1 and dMMR2 - germline); (D) the pMMR1 groups MSI-L and MSS tumors. Colors for each of the groups being compared are shown in the upper right legend box.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111419&req=5

pone-0020465-g002: Plots of principal components from PCA analyses.Horizontal axis corresponds to principal component 1 (PC1), vertical axis corresponds to PC2, and depth axis corresponds to PC3. Points are colored by group status. The percent of variation explained by a particular PC is indicated in the axis label. (A) pMMR1 evaluated by Dukes stage; (B) evaluation by age of onset (pMMR1 - old and pMMR2 - young). (C) evaluation of 2 groupings of dMMR cases (dMMR1 - epigenetic silenced MLH1 and dMMR2 - germline); (D) the pMMR1 groups MSI-L and MSS tumors. Colors for each of the groups being compared are shown in the upper right legend box.
Mentions: The global miRNA expression patterns were then visually examined in various pre-defined tumor sub-groups to determine if these could be distinguished. The PCA plots for these analyses are shown in Figure 2 (data not shown for the hierarchical cluster analyses). Within the pMMR1 group of tumors, there were no apparent discernible differences based on stage, either across all three stages or between any two stages (Stage A not included due to small numbers), or based on gender. Additionally, no separation of groups was visible between tumors with an older age of onset (≥50 y/o, pMMR1) and those with a younger age of onset (<50 y/o, pMMR2). An analysis of tumors within each of the two dMMR subtypes, dMMR1 (somatic) versus dMMR2 (germline), also showed no discernible differences.

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT
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).

Show MeSH
Related in: MedlinePlus