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Abstract

The following reply is in response to the letter by Mahakkanukrauh et al, published on page 1852 in the May issue (Volume 154, Issue 6). The following reply is in response to the letter by Mahakkanukrauh et al, published on page 1852 in the May issue (Volume 154, Issue 6). We would like to thank Mahakkanukrauh et al for their thoughtful letter which raises several important considerations concerning our published article and potential implications for a better understanding of a conceptual basis of our study, and the potential expansion of the screening test using methylated microRNA (miRNA) markers in patients with ulcerative colitis (UC). First, the authors have inquired about the definition of minimum duration for any patient suffering from UC to have any increased risk of colorectal cancer (CRC). Several current guidelines recommend that patients should undergo periodic colonoscopic surveillance with multiple biopsies for earlier diagnosis and treatment of UC-associated CRC (UC-CRC), particularly in the subset of patients with a disease duration of >8 years.1Hata K. et al.Br J Cancer. 2003; 89: 1232-1236Crossref PubMed Scopus (109) Google Scholar, 2Eaden J.A. et al.Gut. 2001; 48: 526-535Crossref PubMed Scopus (2288) Google Scholar However, UC-CRC might manifest in a small proportion of patients within 8 years of disease onset, which was also a finding in our cohort. Recently, Choi et al3Choi C.R. et al.Gut. 2017 Nov 17; ([Epub ahead of print])Google Scholar assessed the severity of microscopic inflammation at each surveillance time point in patients with extensive UC, and clearly demonstrated that cumulative inflammatory burden (sum of average scores) could be used as a predictive marker for risk stratification of patients with UC-CRC. This evidence highlights that the assessment of a cumulative inflammatory score in the colonic mucosa, together with disease duration, might be a more appropriate approach for true risk stratification of patients with UC-CRC. Therefore, for patients with UC, we believe that quantification of methylated miRNA levels in rectal biopsy samples, possibly annually, may help to better represent a cumulative inflammatory score and can, therefore, offer an alternative, less invasive, and cost-effective methodology for risk prediction in patients with UC-CRC. Second, we agree that miRNAs influence the immune system, because accumulating evidence has clarified the role of miRNAs in various aspects of immunity, especially miR-9, -17∼92, -21, -181a, -181c, -146a, and-155. Furthermore, Koukos et al4Koukos G. et al.Gastroenterology. 2013; 145: 842-852.e2Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar have demonstrated that decreased expression of miR-124 could promote inflammation and the pathogenesis of pediatric UC via regulation of STAT3 expression. Although we focused on the DNA methylation in promoter regions of the 5 miRNAs including miR-124 in this study, a negative correlation between methylation and expression levels in these miRNAs was demonstrated. Therefore, dysregulation of miRNA expression via methylation has a theoretical potential to influence patient’s immune status. However, because we did not perform any mechanistic studies in our published article further experiments are needed to clarify the functional role of the miRNAs described in our article for their potential impact on the immune system of patients with UC. Finally, in our study, we did not perform any direct comparison for the miRNA expression profiles between patients with UC-CRC and sporadic CRC; thus, it is difficult to predict how these miRNAs may behave in sporadic CRC. To date, several studies have demonstrated expression profiles of miRNAs in UC-CRC tissues versus normal UC mucosa. For example, Pekow et al5Pekow J. et al.Clin Cancer Res. 2017; 23: 5281-5291Crossref PubMed Scopus (62) Google Scholar performed array-based miRNA profiling, and showed that 6 miRNAs (miR-31, miR-34a, miR-106b, miR-193a-3p, miR-376c, and miR-476) were significantly dysregulated in a dysplasia-carcinoma sequence. Likewise, several studies during the last decade have studied disease-specific miRNA profiling in the adenoma-carcinoma sequence in sporadic CRC patients as well.6Toiyama Y. et al.J Natl Cancer Inst. 2013; 105: 849-859Crossref PubMed Scopus (389) Google Scholar, 7Okugawa Y. et al.Gastroenterology. 2015; 149: 1204-1225.e12Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar Reviewing this evidence independently (colitis vs sporadic CRC), it is obvious that some of the dysregulated miRNAs are shared between these 2 diseases, whereas others are not. Nonetheless, to address the specific comment by the authors, one must do another study directly comparing miRNA expression profiles in the dysplasia-carcinoma versus adenoma-carcinoma cascade. Yuji Toiyama and Yoshinaga Okugawa contributed equally. Methylated MicroRNA Biomarkers for Identifying Ulcerative Colitis–Associated Colorectal CancersGastroenterologyVol. 154Issue 6PreviewWe read with much interest the published article entitled “A Panel of Methylated MicroRNA Biomarkers for Identifying High-Risk Patients with Ulcerative Colitis-Associated Colorectal Cancer” by Toiyama et al.1 At this juncture, we wish to express our scientific views on the published article. Full-Text PDF