Molecular genetics improves the management of hereditary non-polyposis colorectal cancer (original) (raw)
Related papers
European Journal of Cancer, 1995
Hereditary non-polyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC), accounting for approximately 10% of the total CRC burden. HNPCC lacks premonitory physical stigmata, thereby making the family history crucial for diagnosis. Advances in molecular genetics during the past 2 years have led to the cloning of four HNPCC genes (MHS2, MLHl, PMSl and PMSZ). It is now possible to provide presymptomatic DNA testing followed by genetic counselling for gene carriers. Some studies have shown that adenomas in HNPCC are larger, more villous, and have more high grade dysplasia than sporadic cases, suggesting an accelerated adenoma-carcinoma sequence. Given the early age of onset and proximal predominance of CRC, we initiate colonoscopy at age 20-25 years and we recommend that it be performed every l-2 years. The wealth of clinical and molecular genetic knowledge currently available to physicians about HNPCC can be used effectively for cancer control.
Hereditary non-polyposis colorectal cancer: an updated review
Ejso, 2000
Colorectal cancer is the commonest cause of death due to malignancy in non-smokers in the western countries. The two main hereditary types of colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constituting approximately 10% of all cases of colorectal cancer. The main aim of this review is to reappraise the current advances in the genetics and diagnosis of HNPCC. Methods: A Medline search was carried out to identify papers published from 1970 to 1999 on HNPCC. Embase and Cochrane databases were also searched. Reference lists of retrieved articles were carefully searched for additional articles. Results and conclusions: Recent technological advances in the genetics of HNPCC have refined the criteria for diagnosis and management of HNPCC, however current policies regarding the testing of pedigrees are not clearly established. We believe that with the rapid development in this area definitive clinical guidelines will need to be available in future for the management of HNPCC.
Clinical Aspects and Management of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Tumori Journal, 1996
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomical dominant trasmitted disease phenotypically defined according to the “Amsterdam criteria” as follows: at least 3 affected relatives, one of whom first degree relative of other two, at least two successive generations affected. Important cardinal features are: 1 prevalent proximal location of cancers (above splenic flexure); 2 multiple synchronous or methachronous large bowel cancers; 3 early age of onset (<50 years); 4 presence of extracolonic cancers (endometrium, stomach, urinary tract, skin). The treatment is essentially surgical and total colectomy with ileo-rectum anastomosis is already proposed as standard procedure with annual endoscopic examination of retained rectum. The screening of individuals at risk, so determined by the analysis of pedigree or the results of molecular tests, must be performed every 1-2 years by colonoscopy starting around the age of 25 years. In this review are described and analyse...
Hereditary non polyposis colorectal cancer in a random sample of colorectal cancer patients
Acta Medica Academica, 2007
Objective The goal of this prospective research �as to determine genetic and endoscopic changes in patients �ith sporadic colorectal cancer and to diagnose HNPCC. Patients and Methods The group consisted of 40 patients, having colorectal cancer. Colonoscopy �as performed, genetic testing for the loss of heterozygousity and microsatellite instability (MSI). Results HNPCC �as diagnosed using the Amsterdam and Bethesda criteria in the group of sporadic colorectal cancer in 15% of the cases, and exhibited an MSI-H for the chromosome 2p �here the hMSH2 mismatch repair gene is localized. The greatest number of patients �ith sporadic colon cancer and HNPCC displayed Astler-Coller B2 and C1 spread levels. Conclusion The research results indicate that the colonoscopy should be used as a screening method for colorectal cancer. It is necessary to design a colorectal cancer screening program for the general population and high risk individuals. There is a need to form National colorectal cancer, HNPCC and FAP registries.
European Journal of Surgical Oncology (EJSO), 2008
Hereditary Non-polyposis Colorectal Carcinoma is the most frequent genetic disease leading to colon and other malignancies. Recognizing the condition requires extensive family history going back several generations focusing particularly on the types of tumors occurring in the family at different age groups. Methods: In families who met the Amsterdam and Bethesda Criteria, the removed tumor tissue was first examined by immunohistochemistry and microsatellite instability analysis. Subsequently DNA sequencing was performed to detect an underlying Mismatch Repair Gene mutation and multiple ligation dependent probe amplification was applied for recognizing large deletions in Mismatch Repair Genes. Results: In the investigated families 3 pathogen mutations, 1 large deletion and 2 cases of polymorphism were found. There is considerable difference between the families in terms of the types of malignancies and the age in which those appeared. Conclusion: Recognizing families with Hereditary Non-polyposis Colorectal Carcinoma presents great difficulties because of the variety of phenotypes in presentation. Special attention should be paid to small families and those who present with cancer of other than colon origin. Practicing physicians should be made aware of the fact that this disease may have atypical presentations. Follow up of families who have already been screened may be difficult for social, economical or religious reasons.
British Journal of Surgery, 1997
Background Clinical screening is still the first-line approach to identification of families with hereditary non-polyposis colorectal cancer (HNPCC). The need for uniformity of diagnosis of the syndrome, particularly in multicentre studies, led to the establishment of a set of minimum diagnostic criteria, the 'Amsterdam criteria'. It is now known that HNPCC is caused by germline defects in the human mismatch repair genes and DNA predictive testing is possible. Defects in two of the known mismatch repair genes, namely hMSH2 and hMLH1, account for over 90 per cent of mutations found in HNPCC families. Methods Ten families were identified with pedigrees suggestive of HNPCC (that is with a possible dominant inheritance of HNPCC), but in which the Amsterdam criteria were not fulfilled. Using the technique of single-strand conformational polymorphism analysis, samples were screened from an affected member of each of these ten kindreds for germline mutations in the genes hMSH2 and hMLHl. Results Mutations were identified in six families. Of these, there were three missense, one nonsense, one frameshift and one putative splice-site mutation. Three of the mutations were in hMSH2 and three in hMLH1. Conclusion This study demonstrates that all families with a pedigree suggestive of HNPCC should be referred to a geneticist even if the Amsterdam criteria are not fulfilled. A knowledge of the gene carrier status enables targeted surveillance and the possibility of early surgical intervention that could be curative.
TTD consensus document on the diagnosis and management of hereditary colorectal cancer
Clinical and Translational Oncology, 2010
Colorectal cancer is the fi rst cause of cancer in occidental countries if we consider both male and females tumours. In Spain, 26,000 new cases are diagnosed every year. The possibilities of cure are higher if the tumour is diagnosed early. One of the most important risk factors for colorectal cancer is inheritance. Some hereditary syndromes, such as familial adenomatous polyposis (FAP), increase the risk by almost 100% and at a young age. Other more prevalent syndromes, such Lynch syndrome, increase the risk 10-12 times more than in the general population. This article aims at summarising the most important aspects in hereditary colorectal cancer and to be a useful tool to oncologists who work with these patients and their families.
Gastroenterology, 1996
Background & Aims: Hereditary nonpolyposis colorectal hPMS2) responsible for HNPCC has facilitated diagnosis cancer is characterized by early-onset colorectal canof HNPCC and has made it possible to identify carriers cer and the occurrence of various other cancers. The of the mutated gene within a family. 3-7 It has been recent isolation of four mismatch repair genes responestimated that the prevalence of carriers of one of the sible for hereditary nonpolyposis colorectal cancer HNPCC genes among the general population in Western allows for the identification of carriers within affected countries is between 1 of 200 and 1 of 2000. 2 For examfamilies. The purpose of this study was to assess the ple, this means that in The Netherlands (population of age-specific cancer risk in a large series of gene carri-15 million), approximately 15,000 subjects carry this ers. Methods: Thirty-four families were studied by mutagene. These carriers have a risk of ú90% of developing tion analysis. In 19 of these families, pathogenic mutaone of the cancers associated with HNPCC and, therefore, tions were found at hMSH2 or hMLH1. Of 382 relatives, need careful follow-up. However, before recommendation 124 had a mutation in hMLH1 and 86 in hMSH2. Re
British Journal of Cancer, 2004
Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected -that is, with HNPCC-related cancer diagnosis -and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (Po0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.