John Northover

Inherited Susceptibility to Colorectal Adenomas and Carcinomas: Evidence for a New Predisposition Gene on 15q14-q22

BACKGROUND & AIMS The aim of this study was to evaluate the role of known colorectal adenoma and carcinoma susceptibility genes and to locate a novel susceptibility gene in an Ashkenazi family (SM1311) with dominantly inherited predisposition to colorectal adenomas and carcinomas. METHODS Clinicopathologic and family history data were collected. Genetic linkage and mutational analyses were used to investigate the genetic basis of the familys disease. RESULTS Affected members of SM1311 develop multiple tubular, villous, tubulovillous, and/or serrated colorectal adenomas throughout the large bowel, and some develop colon carcinoma. There are no extracolonic features clearly associated with disease in SM1311. We have shown that the familys phenotype does not result from APC mutations (including the I1307K variant) or from genetic changes in the other known genes that predispose to colon cancer. Using genetic linkage analysis, supplemented by allele loss in tumors, we have provided evidence for a new colorectal cancer susceptibility gene, CRAC1 (colorectal adenoma and carcinoma), mapping to chromosome 15q14-q22. CONCLUSIONS We provide evidence for a novel colorectal adenoma and carcinoma susceptibility gene on chromosome 15q14-q22. Further studies are needed to confirm this localization and to evaluate the contribution of CRAC1 to this disease.

Restriction enzyme analysis of mitochondrial DNA in colorectal tumours

Total cellular DNA samples were isolated from 15 colorectal adenocarcinomas, 8 colon adenomas and their adjacent histologically normal colon mucosa. These DNA samples were digested separately with 13 different restriction endonucleases and analysed by Southern blot hybridization using a purified 32P-labelled human mtDNA probe. The fragment patterns from tumour mtDNA were compared to those from corresponding normal mtDNA. No evidence for large deletions, insertions, rearrangements or single base mutations in the detectable regions was detected. This suggests that other mechanisms may be responsible for the changes of colorectal tumour mitochondria.

Surgical aspects of familial adenomatous polyposis

The moderator and participants in this symposium are some of the members of the Leeds Castle Polyposis Group, set up in 1985 to promote cooperative investigation and prospective research in this field. Initial studies have summated data on the group’s screening and surgical practices and their experiences with desmoid disease and upper gastrointestinal neoplasia. The group plans to publish these joint studies in the future; in the meantime we congratulate the participants and moderator in our Symposium for this unique contribution to the literature on this difficult subject.

Staging of colorectal cancer

Moderator: Dr. Jass. The staging of colorectal cancer, a seemingly innocuous and dry subject, has within the last few years become topical and indeed spiked with emotion. A panel of five surgeons and five histopathologists, all with a special interest in colorectal cancer, have been invited to respond to a series of pertinent but fairly open-ended questions. I hope that you will find their answers both thought-provoking and instructive.

Topics in colorectal disease

Fistula-in-ano.- Staging of colorectal cancer.- Faecal incontinence.- Surgical aspects of familial adenomatous polyposis.- Proctography.- Lasers in the treatment of colorectal disease.- Laser therapy in the management of benign and malignant tumours in the colon and rectum.- Laser palliation for rectosigmoid cancers.- Risk factors which determine the long term outcome of Neodymium-YAG laser palliation of colorectal carcinoma.- Endoscopic laser therapy in colorectal cancer.- Photodynamic therapy for colorectal disease.- Laser treatment of intestinal vascular abnormalities.- Commentary: What role do lasers play in the management of colorectal disease.- Pouchitis.- The pathology of the ileal reservoir.- Pouchitis - incidence and characteristics in the continent ileostomy.- The role of endoscopy in pouch monitoring and pouchitis.- Clinical diagnosis.- Bacteriology (I).- Bacteriology (II).- Inflammatory mediators in ulcerative colitis.- Faecal bile acids in pouch and pouchitis patients.- Pouchitis: defining an objective method of diagnosis.- Evacuation and pouchitis.- Ileal pouch motility.- The management of anorectal disease in HIV-positive patients.

Fistula-in-ano

Anal fistula has long been notorious for its tendency to recur after operation and for the great difficulty in achieving a lasting cure while avoiding damage to the mechanism of anal continence. It was these unfavourable circumstances that led some surgeons to take a special interest in its management and were responsible for the establishment by Frederick Salmon in London 152 years ago of St. Mark’s Hospital, which at its inception appropriately bore the name “St. Mark’s Hospital for Fistula and other Diseases of the Rectum”. Anal fistula could thus be regarded as having played a key role in the creation of proctology as a special surgical discipline.