To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

https://cdr.lib.unc.edu/downloads/m900nw503

Comprehensive molecular characterization of human colon and rectal cancer

Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients

According to GLOBOCAN 2018 data, colorectal cancer (CRC) is the third most deadly and fourth most commonly diagnosed cancer in the world. Nearly 2 million new cases and about 1 million deaths are expected in 2018. CRC incidence has been steadily rising worldwide, especially in developing countries that are adopting the "western" way of life. Obesity, sedentary lifestyle, red meat consumption, alcohol, and tobacco are considered the driving factors behind the growth of CRC. However, recent advances in early detection screenings and treatment options have reduced CRC mortality in developed nations, even in the face of growing incidence. Genetic testing and better family history documentation can enable those with a hereditary predisposition for the neoplasm to take preventive measures. Meanwhile, the general population can reduce their risk by lowering their red meat, alcohol, and tobacco consumption and raising their consumption of fibre, wholesome foods, and certain vitamins and minerals.

https://www.termedia.pl/Journal/-41/pdf-34580-10?filename=epidemiology of colorectal.pdf

Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors

Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics1. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

/pdf/recurrent-r-spondin-fusions-in-colon-cancer-1bosryp654.pdf

Recurrent R-spondin fusions in colon cancer

Genome editing applied to human intestinal organoids enables the study of the functional effects of mutations recurrent in human tumors.

Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids

Colorectal cancer is a common but heterogeneous disease, which arises through the accumulation of genetic mutations Knowledge of the molecular basis of colorectal cancer has advanced at a rapid pace in recent years, reflecting progress made in the field of genomic medicine Targeted therapies have come into mainstream use, and the exciting prospect of treatment regimens tailored to the mutation profile of individual tumours is beginning to emerge In order to understand the development and application of the next generation of colorectal cancer treatments, it is important that gastroenterologists have a working knowledge of the pathological mechanisms that drive the disease This review examines our current understanding of the molecular genetics of colorectal carcinogenesis

https://fg.bmj.com/content/flgastro/5/1/26.full.pdf

The molecular genetics of colorectal cancer

A 38-year-old man presented with symptoms of fever and dry cough. There was a past medical history of chronic plaque psoriasis with a single active psoriatic plaque affecting the lateral aspect of the right ankle. The patient was using no regular medication and no topical therapy for psoriasis at

https://casereports.bmj.com/content/bmjcr/13/8/e237367.full.pdf

Guttate psoriasis secondary to COVID-19.

Introduction Colonoscopy is the gold standard modality for investigation of colonic disease. 1 The procedure can be challenging to perform. 1 Complete colonoscopy, defined as intubation of the terminal ileum, neo-terminal ileum, or caecum, should be achieved in greater than 90% of cases on an intention to complete basis. 1 Historically trainees have performed colonoscopy on service lists, and ad hoc training lists and may have had incomplete access to training. 2 Trainees currently working in our unit perform colonoscopy on dedicated training lists prior to JAG certification of independence. We performed a large retrospective study of colonoscopy completion rate, comparing two groups of gastroenterology trainees with consultant Gastroenterologists. Methods 5307 consecutive colonoscopies, from a five-year period in a single centre, were triaged by first endoscopist. Groups identified were 1) consultant Gastroenterologists 2) previous trainees (individuals who trained in the unit in the past, performing colonoscopy on service, adhoc training, and dedicated training lists) 3) Current trainees (employed in the unit at time of study, performing colonoscopy on dedicated training lists). Colonoscopy completion rate, as defined above, was determined for each group. Odds ratios and 95% confidence intervals were calculated to compare the completion rate between groups. Results Results are summarised in the table Conclusion Consultants were more likely to achieve complete colonoscopy than previous trainees, who did not achieve >90% completion rate. In contrast, there was no statistical difference when consultants were compared to current trainees on dedicated training lists. The observed effect is likely to reflect additional allocated time, and immediate consultant trainer availability. Procedures were grouped by first endoscopist. Extent of examination by trainee or trainer in each case is not known: assistance may have been required on a greater proportion of procedures performed on training lists. Colonoscopy completion rate is an important marker of quality. Other indicators include adenoma detection rate, comfort score, and withdrawal time. 1 Inclusion of these indices would provide further comparative performance data. Trainees performing colonoscopy on dedicated training lists delivered comparable completion rates to consultants and outperformed their predecessors. Our data supports dedicated colonoscopy training prior to certification of independence. References Gavin et al . Gut 2013:62:2 242 Bowles et al . Gut 2004:53:2 277 Disclosure of Interest None Declared.

https://gut.bmj.com/content/gutjnl/63/Suppl_1/A40.2.full.pdf

PTU-008 Dedicated Colonoscopy Training Lists Improve Trainee Completion Rates To Match A Consultant Benchmark

A 27-year-old Sudanese woman presented to the emergency department with a 1-week history of lumbar back pain radiating to the buttocks. There was no history of trauma, fever or weight loss. Medical history included ulcerative colitis, maintained in remission with oral mesalazine. On examination, there was midline tenderness over the upper lumbar spine. Neurological examination was normal.

MRI of the lumbar spine (figure 1) demonstrated oedema in …

https://casereports.bmj.com/content/casereports/2013/bcr-2012-008418.full.pdf

Enthesitis in association with inflammatory bowel disease.

The occurrence of colonic polyps is a common phenomenon; however, where there are numerous adenomas or other polyps, and/or the patient is at a relatively young age, an inheritable form of gastrointestinal polyposis should be considered. Patients can present via different referral routes, for example, at colonoscopy where multiple polyps are detected, following a personal diagnosis of colorectal cancer, or by family screening. This article outlines the important considerations in the diagnosis of a polyposis syndrome and key diagnostic features to consider. It will also describe the underlying genetic factors associated with the common polyposis syndromes, including classical familial adenomatous polyposis (FAP), attenuated FAP, MUTYH-associated adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome and serrated polyposis, and the subsequent management of each condition.

https://fg.bmj.com/content/flgastro/5/1/68.full.pdf

Iain Ewing

Papers

The molecular genetics of colorectal cancer

Guttate psoriasis secondary to COVID-19.

PTU-008 Dedicated Colonoscopy Training Lists Improve Trainee Completion Rates To Match A Consultant Benchmark

Enthesitis in association with inflammatory bowel disease.

Gastrointestinal polyposis syndromes for the general gastroenterologist