Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma

Abstract Background Altered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification. Results Three miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis. Conclusions Our study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis

Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview

C.R.C. was funded by the Derek Willoughby Fund for Inflammatory Research. A.L.H. and T.A.G. were funded by Higher Education Funding Council of England

Long-term Oncological Outcome of Segmental Versus Extended Colectomy for Colorectal Cancer in Crohn's Disease: Results from an International Multicentre Study

Background and Aims Crohn's disease increases colorectal cancer risk, with high prevalence of synchronous and metachronous cancers. Current guidelines for colorectal cancer in Crohn's disease recommend pan-proctocolectomy. The aim of this study was to evaluate oncological outcomes of a less invasive surgical approach. Methods This was a retrospective database analysis of Crohn's disease patients with colorectal cancer undergoing surgery at selected European and US tertiary centres. Outcomes of segmental colectomy were compared with those of extended colectomy, total colectomy, and pan-proctocolectomy. Primary outcome was progression-free survival. Secondary outcomes included overall survival, synchronous and metachronous colorectal cancer, and major postoperative complications. Results Ninety-nine patients were included: 66 patients underwent segmental colectomy and 33 extended colectomy. Segmental colectomy patients were older [p = 0.0429], had less extensive colitis [p = 0.0002] and no preoperatively identified synchronous lesions [p = 0.0109]. Median follow-up was 43 [31-62] months. There was no difference in unadjusted progression-free survival [p = 0.2570] or in overall survival [p = 0.4191] between segmental and extended colectomy. Multivariate analysis adjusting for age, sex, ASA score, and AJCC staging, confirmed no difference for progression-free survival (hazard ratio [HR] 1.00, p = 0.9993) or overall survival [HR 0.77, p = 0.6654]. Synchronous and metachronous cancers incidence was 9% and 1.5%, respectively. Perioperative mortality was nil and major complications were comparable [7.58% vs 6.06%, p = 0.9998]. Conclusions Segmental colectomy seems to offer similar long-term outcomes to more extensive surgery. Incidence of synchronous and metachronous cancers appears much lower than previously described. Further prospective studies are warranted to confirm these results

Patient decision-making about emergency and planned stoma surgery for IBD: a qualitative exploration of patient and clinician perspectives

Background: Many IBD patients worry about stoma forming surgery (SFS), sometimes enduring poor bowel-related quality of life to avoid it. Anticipation of SFS and whether expectations match experience is under-reported. This qualitative study explored influences on patients’ SFS decision-making, and compared pre-operative concerns with post-operative outcomes. Methods: We purposively recruited participants with IBD from UK hospital outpatient and community sources, and IBD clinicians from public hospitals. Four focus groups and 29 semi-structured patient participant interviews, and 18 clinician interviews were audio recorded, transcribed, and analysed thematically. Participants had a current temporary, recently-reversed, or permanent stoma, or were stoma naïve. Results: Four themes emerged: Pre-operative concerns and expectations, Patient decision-making, Surgery and recovery, and Long-term outcomes. Participants and clinicians agreed about most pre-operative concerns, that outcomes were often better than expected, and support from others with a stoma is beneficial. Patient decision-making involves multiple factors, including disease status. Some clinicians avoid discussing SFS, and the phrase ‘last resort’ can bias patient perceptions; others recommend early discussion, increasing dialogue when medical management becomes ineffective. The post-operative period is particularly challenging for patients. Stoma acceptance is influenced by personal perceptions and pre- and post-operative clinical and social support. Conclusion: Patients need balanced information on all treatment options, including surgery, from an early stage. Early multi-disciplinary team dialogue about SFS, and contact with others living well with a stoma, could enable informed decision-making. Life with a stoma is often better than anticipated, improving quality of life and control. Ongoing specialist nursing support aids recovery and adjustment