Introduction Background UK and USA surveillance guidelines recommend 3-yearly surveillance for intermediate and higher-risk groups, respectively. To date, no study has examined surveillance needs in this group, which comprises nearly half of patients with adenomas. Aims and objective(s) To identify the optimum frequency of surveillance and assess whether there is substantial heterogeneity in risk; to examine the risks of cancer and advanced adenomas (AA). Method Design and Setting Retrospective, multi-centre cohort study, involving a hospitals dataset drawn from 17 UK NHS hospitals (n = 11,944), and three pooled screening cohorts (n = 2,353). Subjects Patients with intermediate-grade adenoma (s) defined as having 3–4 small adenomas (<10 mm), or 1–2 adenomas, at least one of which is large (≥10 mm). Primary outcomes AA and colorectal cancer (CRC) detected at the first and second follow-up visits, and CRC incidence after baseline and first follow-up. Results Among 4,608 patients with follow-up in the hospital dataset, an increase in interval length was associated with a significant increased odds of AA and CRC at the first follow-up (p < 0.001). Of 1,635 patients attending a second follow-up, a significant association was also found between interval and odds of advanced neoplasia at the second follow-up (p = 0.026). Among 11,944 patients, 168 CRCs occurred during 81,442 person-years of observation time after baseline (206 per 100,000 pyrs, 95% CI 177–240). A single surveillance visit conferred a considerable reduction in risk of CRC after baseline (p = 0.0001). Other independent predictors of CRC were used to devise higher (HIR) and lower (LIR) intermediate risk subgroups, between which there was substantial heterogeneity in risk. A single surveillance exam lowered risk in the HIR subgroup (n = 9,265); however the benefit of surveillance in the LIR (n = 2,679) was unclear. 1,828 intermediate risk patients with at least one follow-up in the pooled screening cohorts were younger, on average, than the hospital cohort. No association was found between findings at follow-up and interval, however, there was evidence of the benefit of surveillance and the LIR and HIR subgroups derived from the hospital dataset were discriminant of CRC risk in the screening participants. Conclusion A surveillance interval of three to four years seems suitable for the majority of intermediate-risk patients. Surveillance lowers future risk of CRC in intermediate risk patients; however there was heterogeneity in risk and surveillance needs, which suggested that a single follow-up may suffice in certain intermediate-risk patients. Disclosure of interest None Declared.

We have audited the effects of these interventions individually and overall.Methods We compared data from 2013 to 2011 to assess the impact of the intervention undertaken. 1.To assess the impact of the change in vetting guidelines, we measured the number of patients with ASA grade 3 or 4 who underwent colonoscopy.2. To assess the impact of the change in patient information, we measured the number of sachets of Klean prep taken by patients and the assessment of the quality of bowel preparation.3. To assess the impact of certain operators stopping performing colonoscopy, we measured the number of operators (excluding trainees) who performed >100 colonoscopies per annum and those with caecal intubation rate (CIR) >90%.4. To measure the combined effect of the interventions, we looked at the combined CIR of all operators within the department. ResultsConclusion All three interventions have caused improvements in measured outcomes.Fewer patients with significant co-morbidities are undergoing colonoscopy.The bowel preparation has improved and there is a statistically significant increase in the mean dose of Klean prep taken.The changes in the number of operators undertaking colonoscopy have allowed fewer operators to do more procedures.Intuitively, practice makes perfect and this along with the other interventions has significantly improved the combined CIR of all operators from 90.21 to 94.54% (p= <0.0001).The implementation of interventions outlined has been rewarding and is an exemplar to other endoscopy units on how to improve key quality outcomes of their colonoscopy practice.

Introduction Patients diagnosed before 50 years of age have a likely strong genetic or environmental aetiological factor. There is good evidence from population studies1 that recessive inheritance is common in young colorectal cancer patients. Methods A cohort of 133 colorectal cancer patients without multiple polyps or a family history of dominant inheritance were diagnosed under the age of 50 years. They were identified and recruited from the Bobby Moore database in the Family Cancer Clinic, St Mark9s Hospital, Harrow. MYH was screened for germline mutations. As these patients fulfilled Bethesda criteria they were tested for hereditary non-polyposis colorectal cancer (HNPCC) by microsatellite instability analysis and immunohistochemistry of mismatch repair proteins. Immunohistochemistry was also performed on β-catenin and P53. Loss of heterozygosity of the APC locus at 5q21–22 was tested using a set of microsatellite markers. Sequencing was used to identify somatic mutations in KRAS and BRAF. Results Forty-four patients (33%) had cancers proximal to the splenic flexure, 79 (59%) distal and had 11 (8%) synchronous colorectal cancers. Thirty-seven patients (28%) had an affected sibling and 33 (25%) patients had a second-degree relative with cancer at any site. The median age of diagnosis of colorectal cancer was 39 years (range 14–49 years of age). Twenty-six patients (20%) were found to harbour sequence variation in the MYH gene but none of these variants were likely to be pathogenic, and there was no difference in the frequency of these compared to a control group of 50 patients. Eighty percent of tumours were found to be microsatellite stable. 20/30 cancers had nuclear localisation of β-catenin and 21/30 had nuclear localisation of P53 antibodies on immunohistochemistry. Loss of heterozygosity of the APC locus at 5q21–22 was present in 14/30 cases. Thus Wnt pathway activation is likely by over half of this group of cancers. Four cancers had BRAF V600E mutations and five had KRAS codon 12 or 13 mutations. Conclusion In a cohort of 133 young colorectal cancer patients without multiple polyps, most tumours demonstrated Wnt pathway activation and other somatic changes consistent with the classical adenoma-to-carcinoma sequence. Germline mutations in the colorectal neoplasia predisposition gene MYH appear to be rare events in such patients. The majority of recessive inheritance in young patients is probably caused by mutations in unknown predisposition genes.

Apc(Min) mice have provided an example of a locus (Modifier of Min1; Mom1) modifying adenoma numbers in the intestines of inbred strains. Linkage analysis located Mom1 on chromosome 4, and further investigation identified secretory phospholipase A2 (Pla2g2a) as a candidate gene. Because of unknown variation introduced by a single founding male mouse, our Min stock, although Pla2g2a(Mom1-s), was not on a pure C57BL/6J background and exhibited several polymorphic loci, including a region on chromosome 18 distal to Apc. Through selective breeding for homozygosity for distal chromosome 18 markers, six recombinant lines that presented with limited intraline variation in adenoma numbers were established. One line (V) showed a particularly severe phenotype (mean adenoma number +/- SEM, 370 +/- 21) compared with the other lines that recorded significantly lower means (3- to 5-fold; P < 10(-3), t test). Intercrosses between lines I and V showed suppression of the severe phenotype in the N1 generation. In N2 (and subsequent) backcrosses, tumor multiplicity depended on the origins of the WT and Min Apc alleles. Mice carrying both alleles from line V had a severe phenotype; others had mild disease very similar to line I (likelihood ratio statistic > 49.0; likelihood of odds > 10; P < 10(-5)). Frequency of allele loss at Apc was increased significantly in adenomas of mice with more severe disease. We propose that a modifier gene close to Apc or structural variation on chromosome 18 modifies polyp numbers in our mice, possibly by altering the frequency of WT Apc allele loss.

MYH-associated polyposis is a recently described, autosomal recessive condition comprising multiple colorectal adenomas and cancer. This disease is caused by germline mutations in the base excision repair (BER) gene MYH. Genes involved in the BER pathway are thus good candidates for involvement in the pathogenesis of sporadic tumors of the large bowel. We have screened a set of 75 sporadic colorectal cancers for mutations in MYH, MTH1, and OGG1. Allelic loss at MYH was also assessed. Selected samples were screened for mutations and allele loss at APC and mutations in p53, K-ras, and beta-catenin. A panel of 35 colorectal cancer cell lines was screened for MYH mRNA and protein expression. One of 75 cancers had bi-allelic germline mutations in MYH and on retrospective analysis of medical records this patient was found to have synchronous multiple small adenomas in addition to carcinoma. No somatic MYH mutations were found and mRNA and protein were expressed in all of our cell lines. There were no clearly pathogenic mutations in MTH1 or OGG1 in any tumor. Bi-allelic germline MYH mutations cause approximately 1 to 3% of unselected colorectal cancers, but appear always to be associated with multiple adenomas. Somatic inactivation of the DNA glycosylases involved in the BER pathway however does not appear to be involved in colorectal tumorigenesis.

Colorectal cancer (CRC) is a significant cause of mortality in Western populations. About 15% of CRC patients report a family history of the disease. Studies on individuals with a genetic predisposition to CRC have been responsible for significant advances in the understanding of this disease. Thus, although developments in molecular biology have been mainly restricted to a minority of individuals with a hereditary background, information obtained from this group may affect the diagnosis and therapy of sporadic CRCs as well. Deficiency in the DNA mismatch repair (MMR) system results in microsatellite instability (MSI). Individuals from hereditary non-polyposis colorectal cancer (HNPCC) kindreds with germline mutations in genes involved in MMR may benefit from clinical screening programs. The higher frequency of MSI in HNPCC than in sporadic tumours suggests that involvement of MMR genes in sporadic adenomas may be uncommon. Consequently

PURPOSE: The aim of this study was to establish the length of telomeres in familial adenomatous polyposis-associated desmoids. METHODS: DNA from 21 desmoids and five desmoid precursor lesions was digested with HinfI and RsaI restriction enzymes. Southern blotting of the resolved fragments was performed, and the membranes were hybridized with a specific probe attached to a chemiluminescent substrate. Terminal restriction fragment lengths were measured. RESULTS: The median terminal restriction fragment length for the desmoids was 8 (range, 6-9.6) vs. 7.7 (range, 6.4-9.9) kb for their controls. Median terminal restriction fragment length for the desmoid precursor lesions was 9 (range, 7.8-10.4) vs. 8.8 (range, 6.8-10.9) kb for their controls. There was no statistically significant difference between samples and their controls. CONCLUSION: Immortality may not be necessary for desmoid development, or there may be other mechanisms maintaining telomere length. Novel treatments involving telomerase inhibition will be inappropriate in the management of desmoids.

Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.

An otherwise healthy 9-month-old boy presented with three slowly enlarging posterior thoraco-lumbar subcutaneous masses found on excision biopsy to be desmoid tumours. When he was 9 years old a similar left temporal mass was removed. A radiograph at that time showed a left mandibular osteoma. 2 years later a right submandibular desmoid (figure) was excised. This recurred and, despite chemotherapy with etoposide, surgery was needed to debulk it. A further local recurrence continued to enlarge despite tamoxifen treatment. He has just completed a course of doxorubicin and dacarbazine and is having radiotherapy. DEPARTMENT OF ERRORDefective homocysteine metabolism as a risk factor for diabetic retinopathy—In this Research letter by S Neugebauer and colleagues (Feb 15, p 473), there were two errors in the table. The serum creatinine values are in μmol/L and the SD value of the HbA1c in diabetic patients with retinopathy is 1·3, not 13. Full-Text PDF

Clinical GeneticsVolume 50, Issue 2 p. 110-111 Exceptions to the rule: individuals with FAP specific CHRPE and mutations in exon 6 of the APC gene K. Pack, Corresponding Author K. PackImperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this authorJ. Smith-Ravin PhD, Corresponding Author J. Smith-Ravin PhDImperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this authorR. K. S. Phillips MS FRCS, Corresponding Author R. K. S. Phillips MS FRCS *Director, St. Mark's Hospital Polyposis Registry.Imperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this authorS. V. Hodgson BM BCh DM FRCP, Corresponding Author S. V. Hodgson BM BCh DM FRCPImperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this author K. Pack, Corresponding Author K. PackImperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this authorJ. Smith-Ravin PhD, Corresponding Author J. Smith-Ravin PhDImperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this authorR. K. S. Phillips MS FRCS, Corresponding Author R. K. S. Phillips MS FRCS *Director, St. Mark's Hospital Polyposis Registry.Imperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this authorS. V. Hodgson BM BCh DM FRCP, Corresponding Author S. V. Hodgson BM BCh DM FRCPImperial Cancer Research Fund Colorectal Cancer Unit St. Mark's Hospital Northwick Park Watford Road Harrow Middlesex HA1 3UJ, UK Tel: + 44–181 235 4250. Fax: + 44–181 235 4277Search for more papers by this author First published: August 1996 https://doi.org/10.1111/j.1399-0004.1996.tb02361.xCitations: 5 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume50, Issue2August 1996Pages 110-111 RelatedInformation

The phenotypic expression in familial adenomatous polyposis (FAP) is variable. This study compares the phenotype of 27 patients with an identical 5 base pair (bp) deletion at codon 1309 with a group of 61 matched patients with FAP where knowledge of specific mutations is not available and with seven other different mutations in 24 subjects. Patients with the codon 1309 deletion have significantly more colorectal polyps at the time of colectomy than age and sex matched FAP controls (p = 0.0001). The median number of polyps in colectomy specimens of patients with the deletion at codon 1309 was 4000 (interquartile (IQ) range 3000-4875), compared with 600 (IQ range 488-1400) in the matched controls. Mutations at codon 1323, 1407, and 233 were also associated with large numbers of polyps. Desmoid disease and extracolonic cancers were more common with the mutation at codon 1309 (p = 0.003). In conclusion, there may be a correlation between a specific germline mutation and the number of large bowel polyps. There is residual heterogeneity in phenotypic expression, however, and this may result from the influence of other genes, specific environmental factors or chance.

Familial adenomatous polyposis is an autosomal dominantly inherited disorder. Mutation studies in the corresponding gene (APC) may provide information for predictive tests for persons at risk in affected families. We report here a new mutation in exon 6 (codon 233) of the APC gene and clinical data in a large family with late onset of the disease in most affected persons.