Double frameshift mutations in APC and MSH2 in the same individual

Heterozygous germline DNA mismatch repair gene mutations are typically associated with HNPCC. Here we report the case of a proband whose father was known for familial adenomatous polyposis. The number of polyps (<10) was not typical of polyposis, therefore the diagnosis of HNPCC was entertained. Microsatellite instability analyses were performed on peripheral blood and biopsy of a right-sided dysplastic adenoma. The tumour tissue showed high-grade instability and subsequently immunohistochemistry showed that neither MSH2 nor MSH6 proteins were expressed in tumour cells. Prophylactic colectomy was performed and an adenocarcinoma developing within the adenoma was diagnosed (pT1N0). Genomic DNA analysis revealed a novel mutation in MSH2 as: a frameshift mutation in exon 7 (c.1,191_1,192dupG). Both parents of the proband were analyzed for MSH2 and APC mutations, and in the father a truncating mutation in exon 15 of APC was identified as del3471-3473GAGA. This mutation was found to be present in the proband. His mother was found to bear the MSH2 exon 7 mutation. At follow-up, the proband was diagnosed with fundic, antral and duodenal adenomas (one fundic adenoma showed low-grade dysplasia). Several tubular rectal adenomas with low-grade dysplasia were excised. The patient later developed an intra-abdominal desmoid tumou

Genotype-phenotype correlative studies in familial colorectal cancer predisposition syndromes

grantor: University of TorontoIt has been estimated that up to 20% of all colorectal cancer (CRC) cases occur due to genetic predisposition. Of these, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) likely account for 5-7% of all CRC. The remainder of familial CRC kindreds is atypical. The aim of this qualitative study was to analyze 31 such atypical families, registered at Mount Sinai Hospital Familial Gastrointestinal Cancer Registry, in order to assess if a proportion of them may be related to one of these syndromes. For this purpose, the strategy to screen these kindreds consisted of using the protein truncation test (PTT) assay to detect germline mutations in the APC, hMLH1 and hMSH2 genes. Seven out of 31 kindreds (22%) were demonstrated to harbour germline mutations in the APC gene; no mutations were detected in DNA mismatch repair genes. The APC mutations were distributed in three regions of the gene: the 5\sp\prime proximal end, within exon 9, and the 3\sp\prime distal end. These mutations correlated with the attenuated adenomatous polyposis coli phenotype. (Abstract shortened by UMI.)M.Sc

Le cancer colo-rectal héréditaire associé aux syndromes polyposiques

This study reviews different aspects of hereditary colorectal cancer associated with three polyposis syndromes: familial adenomatous polyposis, juvenile polyposis coli and Peutz-Jeghers syndrome. All these syndromes share some similarities: low incidence, autosomal dominant inheritance, genetic predisposition to colorectal cancer and/or other extracolonic cancers. Classical familial adenomatous polyposis is clinically defined by the presence of hundreds of adenomatous polyps in the colon and rectum, whereas less than 100 polyps are found in attenuated familial adenomatous polyposis. Without prophylactic colectomy, colorectal cancer develops inevitably by the age of 40. Restorative proctocolectomy with ileal anal-pouch anastomosis is the operation of choice in familial adenomatous polyposis. In juvenile polyposis coli, 50-200 hamartomatous polyps are found in the colon, rectum, stomach and small bowel. Life-time cumulative risk for colorectal cancer is estimated to be 50%. Prophylactic colectomy is required only in cases in which endoscopic surveillance is not able to control polyp development. Hereditary mixed polyposis syndrome is a variant form of juvenile polyposis coli, consisting of multiple mixed adenomatous, hyperplastic and hamartomatous polyps. Peutz-Jeghers syndrome is characterized by multiple hamartomatous polyps located in the small bowel, colon and stomach. Small bowel follow through and colonoscopy is advised for surveillance. Surgery is warranted only in cases of polyps larger than 1 cm. The causative genes of these syndromes have been cloned. Molecular genetic testing of affected and at-risk individuals is proposed in order to advise surveillance and management

Le cancer colo-rectal héréditaire sans polyadénomatose associée

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition in which affected individuals develop colorectal cancer or extracolonic cancer, most commonly endometrial, at an early age. Recent advances in molecular genetics have led to the identification of a germline mutation of DNA mismatch-repair genes to be responsible for the majority of HNPPC cases. Since clinical screening of gene carriers can help to prevent cancer, it is important to devise strategies applicable to this syndrome. Recommendations for current management, especially screening and surgical treatment are under study, as they have not yet been clearly established. This paper reviews the clinical presentation, the molecular genetic diagnosis and therapeutic approaches of this syndrome including the controversies concerning prophylactic colectomy for cancer or gene carriers

Bilaterale Nebennierenhamorrhagie nach vorderer tiefer Rektumresektion. Fallbericht mit Literaturubersicht

Adrenal insufficiency due to bilateral adrenal hemorrhage is a rare but potentially life-threatening postoperative complication. The difficulty lies in making a timely diagnosis, as the symptoms are often unspecific and similar to those presented by other, more common postoperative complications. We report the case of a 71-year-old patient presenting bilateral adrenal hemorrhage following an otherwise uncomplicated low anterior rectum resection for a villous adenoma of the middle rectum

Genetic testing and surgical decision making in hereditary colorectal cancer

Hereditary colorectal cancer results from specific genetic alterations. The causative genes for familial adenomatous polyposis, juvenile polyposis, Peutz-Jeghers syndrome, and hereditary nonpolyposis colorectal cancer have been cloned and characterized within the past decade. Genetic testing has therefore become more widely used to confirm the clinical diagnosis of each of those syndromes, to provide adequate surveillance, to allow screening of at-risk family members, and to help the surgeon in surgical decision making. The aim of this review is to analyze the importance of genetic testing in view of the clinical and surgical management of those gene-carriers individuals, and to discuss how should the surgeon integrate genetic testing in the evaluation of such patients