Search

BACKGROUND AND AIMS: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. PATIENTS AND METHODS: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. RESULTS: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. CONCLUSIONS: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases. [ABSTRACT FROM AUTHOR]

Presents a response by G. Ponti, to a letter to the editor about his article "Diagnosis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)."

The large majority of mutations causing hereditary nonpolyposis colorectal cancer (HNPCC) occurs in hMLH1 or hMSH2 genes, but recent observations have shown that other genes can be involved. The aim of this study was to evaluate the role of hMSH6 gene in HNPCC, through an immunohistochemical approach. 28 colorectal cancer patients with clinical diagnosis of HNPCC or suspected HNPCC were selected. Immunohistochemical studies of hMSH6, hMLH1, and hMSH2 were carried out in paraffin embedded tumour samples. Immunoperoxidase staining was carried out with the NEX-ES, Automatic System. Monoclonal antibodies to hMLH1 and hMSH2 proteins were used at 1:40 dilution; monoclonal antibody to hMSH6 protein was used at 1:2000 dilution. Each tumour sample was tested for microsatellite instability (MSI). Immunohistochemical expression of hMSH6 lacked in 7 of 28 tumours. In 4 cases, absence of hMSH2 expression was associated. The patients (mean age 56.6 years) were all affected by rightsided colon cancer, frequently mucinous and MSI+. Three patients were from HNPCC families fulfilling Amsterdam Criteria I or II. In 2 cases Muir-Torre syndrome (MTS) could be diagnosed, whereas the other 2 were suspected HNPCC. In almost all the pedigrees, an excess of extracolonic tumours was observed: interestingly, in both MTS patients, colorectal cancers and sebaceous dermatologic lesions showed the same immunohistochemical pattern. The complete gene sequencing was carried out in 3 of 7 patients: two hMSH6 and one hMSH2 frameshift mutations leading to a stop codon with a truncated protein were detected. In conclusion, hMSH6 mutations could characterise a subset of families with hereditary colorectal cancer. Altered hMSH6 expression (even if often associated with lack of hMSH2 protein), MSI+, proximal Iocalisation, later age at diagnosis, and the association with extracolonic tumours, seem to be features of suspicion for the presence of hMSH6 mutations. [ABSTRACT FROM AUTHOR]

Although many factors contribute to the development of colorectal tumours, the only clearly identified aetiological factors include inheritance (Lynch syndrome (HNPCC) and familial polyposis (FAP)), inflammatory bowel diseases (ulcerative colitis and Crohn's disease, IBD), papillomavirus and AIDS (HIV). Purpose: To find our what proportion of colorectal malignancies can be attributed to each of these specific factors. Patients and Methods: Data ora colorectal cancer registry have been analysed, over a period of 15 years, during which nearly 2500 cases were recorded. In patients with clinical suspicion of hereditary tumours, microsatellite instability was assessed, and in positive families constitutional mutations of the main mismatch repair genes (hMSH2, hMLH1, hMSH6) were evaluated by single strand conformation polymorphism and sequencing. Results: IBD, FAP, and AIDS were rare causes of colorectal cancer (3, 3 and 1 cases, respectively). Anal squamous carcinoma (attributed to papillomavirus infection) developed in 27 patients (1.0%). In 58 patients (from 34 families) a clinical diagnosis of HNPCC could be established (2.4% of the total). Altogether, cases with a know aetiology (N = 92) accounted for only 3.7% of all patients. Microsatellite instability was found in 15 HNPCC families, while germ line mutations in one of the mismatch repair genes were detected in 6 families (12 patients, 0.5% of the total). Microsatellite positive families, regardless the mutational status, were clinically similar, thus suggesting an involvement of the mismatch repair system even when mutations were not detected. Conclusion: The study suggests that the aetiology of colorectal neoplasms remains elusive in the large majority of cases. Among specific causes, HNPCC represents by far the most frequent. However, by using a population based approach, constitutional mutations of the main genes responsible for HNPCC can be detected in only 20% of the cases. [ABSTRACT FROM AUTHOR]