Hereditary colorectal cancer : clinical and biological consequences of known and new genes, as well as modifiers

摘要: Each year 3500 people in Switzerland are diagnosed with colorectal cancer, approximately 51.8 and 34.3 per 100’000 inhabitants for males females, respectively. Those patients a familial risk ie. they haveor more first or second degree relatives account 20 percent of all affected patients, whereas roughlyto 10 the total annual burden cancer is mendelian nature – that is, it inherited an autosomal dominant manner. This thesis has focused on genotype-phenotype correlations two hereditary syndromes, nonpolyposis (HNPCC) adenomatous polyposis (FAP) attempt to optimise selection criteria individuals, establish sensitivity specificity different screening methods, investigate relatively new gene associated multiple adenoma carcinoma phenotype assess role modifier locus chromosome 1p33-36. Since only limited data available which detail value HNPCC referral combination microsatellite instability (MSI) testing various mutation 222 unrelated Swiss were studied order (i) phenotypic molecular differences between belonging groups, (ii) determine diagnostic accuracy procedures employed identifying individuals mismatch repair (MMR) alterations. The Bethesda Guidelines (BG) proved be superior compared Amsterdam Criteria I/II (AC I/II) alone, MMR Based evaluation techniques this study, suggested MSI analysis combined immunohistochemistry subsequent mutational positively scored encompassing both DNA mRNA-based technique, should conducted optimal rates detection. Investigations subsequently continued attempts further characterise by comparing 46 carriers 84 alteration negative ultimately aid identification carriers. Ninety-four positive classified BG) 76% individuals. Mutation also younger at time their CRC diagnosis, had often proximally located CRCs, higher prevalence syn-/metachronous CRCs frequently extracolonic manifestations. Using such distinguish from mutation negative clinicians may aided preselection genetic surveillance, subsequently, genetic counselling. In light results recent studies, implicating germline mutations MYH multiple colorectal phenotype, was purpose study correlate MYH APC-negative (n=65) any genotype-phenotype optimisation clinical prevention strategies. An optimised protocol rapid sensitive via high performance liquid chromatography (DHPLC) established. Thirteen (20%) were identified as carriers, 7 (54%) biallelic mutations. Aside from previously reported mutations, 3 apparently novel alterations established patients with phenotype. phenotypical characteristics investigated were similar, no statistically significant genotype, hence, and counsellors advised screen displaying tens hundreds of colorectal adenomas, family history consistent recessive inheritance. FAP typically display considerable inter- intra-familial heterogeneity, which represents major problem counselling APC Min mouse model indicated putative disease 4, syntenic to human 1p35-36. Furthermore, base-excision gene MYH, maps 1p33-34 region, have been described multiple adenomas, pointing possible FAP. Here, re-assessment one of largest FAP kindreds published, previously used linkage mapping 1p35- 36, documented. latest information, additional carriers and polymorphic markers, fine-mapping critical region well the MYH performed. These investigations significantly excluded 1p33-36 as a extracolonic kindred. The indicate candidate regions necessary to identify