Increased mucosal expression of miR-215 precedes the development of neoplasia in patients with long-standing ulcerative colitis.

Joel Pekow,Haider I Haider,Marc Bissonnette,Katherine Meckel,Zifeng Deng,David T Rubin,Urszula Dougherty,John Hart

doi:10.18632/oncotarget.25065

Joel Pekow, Haider I Haider + Show 6 more

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https://doi.org/10.18632/oncotarget.25065

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Journal: Oncotarget	Publication Date: Apr 17, 2018
Citations: 8	License type: cc-by

Affiliation: University of Chicago

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Identification of biological markers predicting the onset of neoplasia in patients with long-standing ulcerative colitis (UC) could allow for risk stratification in this population. In this study, we retrospectively identified subjects with chronic UC who developed colon neoplasia (n = 16) matched to UC patients who never developed neoplasia. RNA was extracted from archived colonic biopsies obtained at an interval of 1–2 years prior and 3–5 years prior to the onset of neoplasia. miRNA expression was assessed using Nanostring arrays in 12 subjects, and significantly up-regulated miRNAs were evaluated by real time pcr in the entire cohort of patients. Expression of miR-215 was also assessed in UC-associated colon cancers and compared to p53 expression. By array analysis, there were 17 significantly down-regulated and 7 significantly up-regulated miRNAs in subjects who later developed neoplasia. miR-215 was significantly up-regulated both 1–2 years prior to the onset of neoplasia (3.5-fold, p < 0.001) and 3–5 years prior to the onset of neoplasia (5.4-fold, p = 0.007). miR-215 expression was also increased in UC-associated colon cancers (5.3-fold, p = 0.03) and adjacent non-dysplastic UC tissue (6.2-fold, p = 0.02). p53 was expressed in 20% of patients prior to the onset of neoplasia and in 67% of UC-associated colon cancers, although was not correlated with miR-215 expression. Our data demonstrates that expression of miR-215 can discriminate patients who progressed to neoplasia from non-progressors as early as 5 years prior to the diagnosis of neoplasia, supporting that this and perhaps other miRNAs could serve as predictive biomarkers to risk stratify patients with chronic UC.

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Patients with long-standing ulcerative colitis (UC) are at increased risk for colorectal cancer (CRC) [1,2,3]
As p53 mutations are described to occur prior to the onset of neoplasia in patients with chronic ulcerative colitis [30], we investigated expression of mutant p53 in non-dysplastic mucosa from patients in this cohort who progressed to neoplasia compared to those who never progressed using the same tissues that were utilized to assess miRNA expression. 20% of progressors had positive expression for p53 compared to 0% of nonprogressors (p = 0.06) (Figure 4A)
We demonstrate that mucosal miRNA expression levels in UC patients from nondysplastic tissue can distinguish patients who later are diagnosed with colorectal neoplasia

Summary

Introduction

Patients with long-standing ulcerative colitis (UC) are at increased risk for colorectal cancer (CRC) [1,2,3]. Unlike sporadic colon cancer, which is typically isolated and arises in non-dysplastic mucosa, UC-associated neoplasia is often multifocal. This finding reflects a broader ‘field effect’ of involved mucosa at risk in patients with IBD. We have demonstrated that gene and miRNA expression changes occur in non-dysplastic mucosa from UC patients harboring a remote neoplastic lesion [15, 16]. These molecular changes can, serve as surrogate markers of dysplastic changes in other areas of the colon

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