[Hereditary non polyposis colorectal cancer]. / Les cancers coliques familiaux sans polypose ou syndrome HNPCC.

Hereditary non polyposis colorectal cancer (HNPCC) is characterized by an excess of early colorectal carcinomas, preferentially located on the ascending colon, associated with a variety of extracolonic cancers. The recent demonstration of germline mutations in DNA mismatch repair genes in HNPCC patients enhanced the interest due to the syndrome. Molecular genetic testing of HNPCC has become available, and should help physicians to recommend specific modalities for the surveillance and the management of patients with such a high cancer risk.

Extensive molecular screening for hereditary non-polyposis colorectal cancer.

The genetic abnormalities underlying hereditary non-polyposis colorectal cancer (HNPCC) are germline mutations in one of five DNA mismatch repair genes or in the TGFbetaRII gene. The aim of our study was to evaluate the significance of simple tests performed on tumours to select appropriate candidates for germline mutational analysis. We studied three groups of patients, HNPCC kindreds fulfilling the International Collaborative Group (ICG) criteria (n = 10), families in which at least one of the criteria was not satisfied (n = 7) and sporadic colorectal cancer (CRC) diagnosed before the age of 50 (n = 17). We searched for microsatellite instability (MSI), presence of hMSH2 and hMLH1 germline mutations, expression of hMSH2, hMLH1 and p53 proteins in tumoural tissue samples by immunostaining. Fifteen out of 17 (88%) of HNPCC and incomplete HNPCC cases were MSI and eight pathogenic germline mutations in hMSH2 or hMLH1 were detected in these two groups (53%). All the 17 early-onset sporadic cases were MSS and no germline mutations were detected among the seven investigated cases. Thirteen out of 15 (81%) familial cases were MSI and p53 protein-negative, whereas 13/14 (93%) sporadic cases were MSS and strongly p53 protein-positive. This extensive molecular investigation shows that simple tests such as MS study combined with hMSH2 and hMLH1 protein immunostaining performed on tumoural tissues may provide valuable information to distinguish between familial, and probably hereditary, and sporadic CRC cases.

[Muir-Torre syndrome and familial colorectal cancer: 2 families with molecular genetic analysis]. / Syndrome de Muir-Torre et cancer colorectal familial: deux familles avec étude génétique moléculaire.

INTRODUCTION: The Muir-Torre Syndrome is a rare genodermatosis, defined by the occurrence of cutaneous tumors (such as sebaceous adenomas, epitheliomas, or carcinomas, and/or keratoacanthomas), and internal malignancies. Recently, molecular analysis in hereditary non polyposis colorectal cancer demonstrated a common genetic basis, linking these two disorders, with the observation of germline mutations in the hMSH2 gene (one of the DNA mismatch repair system genes) in both syndromes. Such molecular demonstration of a single nosological entity should be clinically used to improve the indications of molecular testings in oncogenetics, still restricted to highly stringent criteria for hereditary non polyposis colorectal cancer. CLINICAL CASES: We identified three patients from two different families, who fulfilled the criteria for both Muir-Torre Syndrome and hereditary non polyposis colorectal cancer. The search of a germline mutation of the hMSH2 gene was performed on an affected member from each family, and their relatives with their informed consent. Within each family, all individuals with colorectal cancer were carriers of the same mutation. In the first family, this mutation was a pathogenic microinsertion, usable for predictive testing. In the second family, a missense mutation was identified, requesting further demonstration of its pathogenicity before its use in a predictive purpose. CONCLUSIONS: The diagnosis of cutaneous tumors compatible with Muir-Torre syndrome should lead the dermatologist to suspect an hereditary non polyposis colorectal cancer that should bring to an oncogenetic approach: personnal and familial history of colorectal cancer, molecular analysis, recommendations for colonoscopic screening in at-risk relatives. In the case of a colorectal cancer at a young age, or in the case of familial cases, the gastroenterologist should screen for cutaneous lesions of Muir-Torre syndrome, which could add a criteria for an hereditary syndrome, and lead to molecular oncogenetic analysis.

Delineation of the insulin-responsive sequence in the rat cytosolic aspartate aminotransferase gene: binding sites for hepatocyte nuclear factor-3 and nuclear factor I.

Expression of the rat cytosolic aspartate aminotransferase gene is stimulated by glucocorticoids and repressed by insulin in the liver. The regulation by insulin and part of the glucocorticoid effect are mediated by a distal region in the promoter. A 142 bp fragment (-1844 to -1702) confers hormonal sensitivity to the heterologous thymidine kinase promoter in transient-transfection assays in H4IIEC3 hepatoma cells. Footprinting and gel-shift assays showed that several nuclear proteins bind to this region at conserved CCAAT-enhancer binding protein (C/EBP), activator protein (AP-1) and E-box sequences. Hepatocyte nuclear factor-3alpha (HNF-3)alpha and beta bind to sequences upstream of a glucocorticoid-responsive element (GRE) half-site as demonstrated by supershift experiments. Nuclear factor I (NFI)-like proteins bind downstream of the GRE half-site. These sites around the GRE motif overlap with five insulin responsive element (IRE) -like sequences (TG/ATTT). The effect of insulin was not prevented by any single mutation in the IRE-like sites. However, mutation of two IRE sites (namely IREc and d) prevented the insulin effect although only marginally affecting the glucocorticoid effect. The results suggest that the effect of insulin is due to a complex interplay of factors requiring the synergistic contribution of at least two sites and underline the contribution of HNF-3 and NFI-like proteins.