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Differential expression of microRNAs in preneoplastic gastric mucosa.

Link A, Schirrmeister W, Langner C, Varbanova M, Bornschein J, Wex T, Malfertheiner P - Sci Rep (2015)

Bottom Line: Gastric normal mucosa shows a unique expression pattern for miR-21, miR-155 and miR-223, which is specific for different regions.Using miRNA expression we calculated a score that allowed us to discriminate patients with AG from subjects with normal mucosa with high diagnostic accuracy in testing and validation cohorts reproducibly.However, differences of miRNA expression between the gastric antrum and the corpus need to be considered in future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.

ABSTRACT
Gastric carcinogenesis is a multifactorial H.pylori-triggered dynamic process that goes through a cascade of preneoplastic conditions. The expression of miRNAs in the stomach with regard to preneoplastic precursor conditions and H.pylori infection has not been investigated systematically. In this prospective proof-of-principle study, we evaluated the miRNA expression in gastric antrum and corpus mucosa from patients with chronic non-atrophic gastritis (CNAG), atrophic gastritis (AG), and GC compared to controls. Gastric normal mucosa shows a unique expression pattern for miR-21, miR-155 and miR-223, which is specific for different regions. In correlation with progression of Correa's cascade and H.pylori infection, we observed a gradual increase in miR-155 and miR-223 both in corpus and antrum and miR-21 only in the antrum mucosa. Using miRNA expression we calculated a score that allowed us to discriminate patients with AG from subjects with normal mucosa with high diagnostic accuracy in testing and validation cohorts reproducibly. In summary, the expression pattern of miRNAs in the gastric mucosa is gradually increased with progression of Correa's cascade and H.pylori infection, suggesting miRNAs as potential biomarkers for preneoplastic precursor conditions. However, differences of miRNA expression between the gastric antrum and the corpus need to be considered in future studies.

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miRNA expression scores distinguish atrophic gastritis from normal mucosa.(A and B) ΔCt-values of miR-21, miR-155, and miR-223 were added together to calculate the ∑ ΔCt-value following normalization of each miRNA to RNU6b. Various summary scores have been used to calculate receiver operating characteristics for (C) corpus and (D) antrum. N – controls (n = 19); CNAG – chronic non-atrophic gastritis (n = 25); AG – atrophic gastritis (n = 20). ***-p < 0.0001; **-p < 0.001; *- p < 0.05.
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f4: miRNA expression scores distinguish atrophic gastritis from normal mucosa.(A and B) ΔCt-values of miR-21, miR-155, and miR-223 were added together to calculate the ∑ ΔCt-value following normalization of each miRNA to RNU6b. Various summary scores have been used to calculate receiver operating characteristics for (C) corpus and (D) antrum. N – controls (n = 19); CNAG – chronic non-atrophic gastritis (n = 25); AG – atrophic gastritis (n = 20). ***-p < 0.0001; **-p < 0.001; *- p < 0.05.

Mentions: Based on the observation that the studied miRNAs are increased in gastric preneoplastic precursor conditions, we questioned if a simple and easily applicable miRNA expression score might have diagnostic potential and therefore be useful for the risk stratification of patients with mucosal abnormalities. For this purpose, we combined ΔCt-values of the studied miRNAs into a single summary score for different combination of miRNAs with each other (ΔCtmiR-21 + ΔCtmiR-155 + ΔCtmiR-223), creating the pooled miRNA expression score (ΣΔCt-value, Figure 4A and B), which may facilitate the generation of individualized risk stratification. The ΣΔCt-score was significantly higher in CNAG and AG compared to N both in corpus (−11.37 ± 1.76 vs. −9.61 ± 1.47 vs. −8.12 ± 2.26, p < 0.0001; for N, CNAG and AG, respectively) and antrum (−15.69 ± 1.53 vs. −12.86 ± 2.39 vs. −10.97 ± 1.79; p < 0.0001). Translating this into the fold change, the mean score difference between AG and N is approximately 8-fold for corpus and 10-fold for antrum. To evaluate the diagnostic accuracy of this score, we performed a ROC-curve analyses for various combinations of the scores for corpus and antrum independently (ΔCtmiR-21 + ΔCtmiR-155 + ΔCtmiR-223; ΔCtmiR-21 + ΔCtmiR-155; ΔCtmiR-21 + ΔCtmiR-223 and ΔCtmiR-155 + ΔCtmiR-223). Especially the combination of all 3 miRNAs reached area under the curve (AUC) values of 0.9025 (95% CI 0.802–1.003) for the corpus, and 0.985 (95% CI 0.9577–1.012) for the antrum (Figure 4C and D). Among available tools, OLGA and OLGIM staging systems have been proposed for prediction of progression for gastric cancer development. To evaluate if the miRNA summary score may potentially be useful for prediction of GC development we compared its performance with the OLGA and OLGIM scores in our patients. We show that there is significant correlation between the extent of atrophic gastritis and intestinal metaplasia defined by OLGA and OLGIM scores, respectively, and the miRNA expression score in gastric mucosa (Supl. Figure 4A and B).


Differential expression of microRNAs in preneoplastic gastric mucosa.

Link A, Schirrmeister W, Langner C, Varbanova M, Bornschein J, Wex T, Malfertheiner P - Sci Rep (2015)

miRNA expression scores distinguish atrophic gastritis from normal mucosa.(A and B) ΔCt-values of miR-21, miR-155, and miR-223 were added together to calculate the ∑ ΔCt-value following normalization of each miRNA to RNU6b. Various summary scores have been used to calculate receiver operating characteristics for (C) corpus and (D) antrum. N – controls (n = 19); CNAG – chronic non-atrophic gastritis (n = 25); AG – atrophic gastritis (n = 20). ***-p < 0.0001; **-p < 0.001; *- p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317705&req=5

f4: miRNA expression scores distinguish atrophic gastritis from normal mucosa.(A and B) ΔCt-values of miR-21, miR-155, and miR-223 were added together to calculate the ∑ ΔCt-value following normalization of each miRNA to RNU6b. Various summary scores have been used to calculate receiver operating characteristics for (C) corpus and (D) antrum. N – controls (n = 19); CNAG – chronic non-atrophic gastritis (n = 25); AG – atrophic gastritis (n = 20). ***-p < 0.0001; **-p < 0.001; *- p < 0.05.
Mentions: Based on the observation that the studied miRNAs are increased in gastric preneoplastic precursor conditions, we questioned if a simple and easily applicable miRNA expression score might have diagnostic potential and therefore be useful for the risk stratification of patients with mucosal abnormalities. For this purpose, we combined ΔCt-values of the studied miRNAs into a single summary score for different combination of miRNAs with each other (ΔCtmiR-21 + ΔCtmiR-155 + ΔCtmiR-223), creating the pooled miRNA expression score (ΣΔCt-value, Figure 4A and B), which may facilitate the generation of individualized risk stratification. The ΣΔCt-score was significantly higher in CNAG and AG compared to N both in corpus (−11.37 ± 1.76 vs. −9.61 ± 1.47 vs. −8.12 ± 2.26, p < 0.0001; for N, CNAG and AG, respectively) and antrum (−15.69 ± 1.53 vs. −12.86 ± 2.39 vs. −10.97 ± 1.79; p < 0.0001). Translating this into the fold change, the mean score difference between AG and N is approximately 8-fold for corpus and 10-fold for antrum. To evaluate the diagnostic accuracy of this score, we performed a ROC-curve analyses for various combinations of the scores for corpus and antrum independently (ΔCtmiR-21 + ΔCtmiR-155 + ΔCtmiR-223; ΔCtmiR-21 + ΔCtmiR-155; ΔCtmiR-21 + ΔCtmiR-223 and ΔCtmiR-155 + ΔCtmiR-223). Especially the combination of all 3 miRNAs reached area under the curve (AUC) values of 0.9025 (95% CI 0.802–1.003) for the corpus, and 0.985 (95% CI 0.9577–1.012) for the antrum (Figure 4C and D). Among available tools, OLGA and OLGIM staging systems have been proposed for prediction of progression for gastric cancer development. To evaluate if the miRNA summary score may potentially be useful for prediction of GC development we compared its performance with the OLGA and OLGIM scores in our patients. We show that there is significant correlation between the extent of atrophic gastritis and intestinal metaplasia defined by OLGA and OLGIM scores, respectively, and the miRNA expression score in gastric mucosa (Supl. Figure 4A and B).

Bottom Line: Gastric normal mucosa shows a unique expression pattern for miR-21, miR-155 and miR-223, which is specific for different regions.Using miRNA expression we calculated a score that allowed us to discriminate patients with AG from subjects with normal mucosa with high diagnostic accuracy in testing and validation cohorts reproducibly.However, differences of miRNA expression between the gastric antrum and the corpus need to be considered in future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.

ABSTRACT
Gastric carcinogenesis is a multifactorial H.pylori-triggered dynamic process that goes through a cascade of preneoplastic conditions. The expression of miRNAs in the stomach with regard to preneoplastic precursor conditions and H.pylori infection has not been investigated systematically. In this prospective proof-of-principle study, we evaluated the miRNA expression in gastric antrum and corpus mucosa from patients with chronic non-atrophic gastritis (CNAG), atrophic gastritis (AG), and GC compared to controls. Gastric normal mucosa shows a unique expression pattern for miR-21, miR-155 and miR-223, which is specific for different regions. In correlation with progression of Correa's cascade and H.pylori infection, we observed a gradual increase in miR-155 and miR-223 both in corpus and antrum and miR-21 only in the antrum mucosa. Using miRNA expression we calculated a score that allowed us to discriminate patients with AG from subjects with normal mucosa with high diagnostic accuracy in testing and validation cohorts reproducibly. In summary, the expression pattern of miRNAs in the gastric mucosa is gradually increased with progression of Correa's cascade and H.pylori infection, suggesting miRNAs as potential biomarkers for preneoplastic precursor conditions. However, differences of miRNA expression between the gastric antrum and the corpus need to be considered in future studies.

Show MeSH
Related in: MedlinePlus