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HNPCC Families (hnpcc + family)
Selected AbstractsDeletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome,HUMAN MUTATION, Issue 2 2009Marietta E. Kovacs Abstract Several different genetic alterations in the etiology of Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) are known, mostly point mutations and genomic rearrangements in 1 of at least 3 mismatch-repair (MMR) genes. However, no susceptibility factor has yet been identified in a significant part (30,50%) of clinicopathologically well-defined HNPCC families, suggesting the presence of other predisposing mechanisms. In a set of probands from 27 Lynch syndrome families who lacked evidence of a germline mutation in either the MSH2 or MLH1 gene, we performed genomic deletion screening with the use of multiplex ligation-dependent probe amplification (MLPA) and sequencing. We used immunohistochemistry (IHC) and microsatellite instability (MSI) analyses on samples of the probands of all families. Comparative analysis of mRNA transcripts was performed on blood leukocyte,derived samples from mutation carriers and noncarrier controls. We report that large germline deletions encompassing the last exons of the TACSTD1 gene, upstream of MSH2, cosegregate with the HNPCC phenotype in 19% (5/27) of families tested. The tumors of the carriers show high-level MSI and MSH2 protein loss. We show that these deletions, by removing the transcriptional termination sequences of the upstream gene, give rise to multiple TACSTD1/MSH2 fusion transcripts. Our results provide evidence that deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Thus, analysis of the 3, region of the TACSTD1 gene should be included in the routine mutation screening protocols for HNPCC. Hum Mutat 30, 197,203, 2009. © 2009 Wiley-Liss, Inc. [source] Novel MLH1 mutations and a novel MSH2 polymorphism identified by SSCP and DHPLC in Portuguese HNPCC families,,HUMAN MUTATION, Issue 5 2003G. Isidro Abstract Mismatch repair genes MSH2 and MLH1 are the two major genes implicated in hereditary nonpolyposis colorectal cancer. For the past years, we have successfully searched for mutations in both genes in affected Portuguese families, by SSCP and DNA sequencing analysis but because of the advantages that DHPLC offers, we have established conditions in our laboratory to use this new method. While screening for mutations by both methods, in 35 individuals belonging to HNPCC Portuguese families, 4 novel MLH1 mutations (c.307-1G>C; c.1023delG [p.R341fsX366]; c.2154_2155delCA [p.H718fsX721], c.2154_2155dupCA [p.I719fsX782]), an unclassified variant (c.-28A>T) and one silent MSH2 polymorphism (c.2766T>C) have been identified. © 2003 Wiley-Liss, Inc. [source] Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndromeINTERNATIONAL JOURNAL OF CANCER, Issue 4 2007Laura Renkonen-Sinisalo Abstract The estimated lifetime risk for endometrial carcinoma (EC) in hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is 32,60%, thus supporting surveillance. The survival rate of EC patients is, however, favourable questioning the need for surveillance. Yet, the effectiveness of gynecological surveillance remains to be shown. The 2 previously published studies were based on transvaginal ultrasound (TVUS) alone. Intrauterine biopsy has not been tested in surveillance for EC in HNPCC families. The effect of gynecological surveillance was evaluated among 175 Finnish mutation carriers. During 759 person years at risk, there were 503 surveillance visits including TVUS and intrauterine biopsy of endometrium at 94% and 74% of the visits, respectively. EC occurred in 14 cases, 11 of which were diagnosed by surveillance, 8 by intrauterine biopsies. TVUS indicated only 4 EC patients but missed 6 other cases. Intrauterine sampling detected 14 additional cases of potentially premalignant hyperplasia. The stage distribution and survival tended to be more favorable in the 14 EC cases of the surveilled group (no deaths) than in the group of 83 symptomatic mutation carriers of whom 6 died of EC, but with no statistical significance. Four cases of ovarian cancer occurred but none was detected by surveillance in TVUS examinations. In conclusion, EC surveillance in HNPCC seems more effective with endometrial biopsies than with TVUS alone. A definite improvement in survival remains to be shown. The detection of early cancer stages and premalignant lesions offers the opportunity to avoid extensive adjuvant treatment. © 2006 Wiley-Liss, Inc. [source] Evidence for an age-related influence of microsatellite instability on colorectal cancer survivalINTERNATIONAL JOURNAL OF CANCER, Issue 6 2002Susan M. Farrington Abstract It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n = 118; non-age-selected, n = 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p , 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression. © 2002 Wiley-Liss, Inc. [source] Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCCCLINICAL GENETICS, Issue 3 2007B Roncari A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL1 or MSH2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT25 and BAT26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC. [source] Putative common origin of two MLH1 mutations in Italian-Quebec hereditary non-polyposis colorectal cancer familiesCLINICAL GENETICS, Issue 2 2004I Thiffault Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3,5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin. [source] The impact of new screening protocol on individuals at increased risk of colorectal cancerCOLORECTAL DISEASE, Issue 7 2007T. Mak Abstract Objective, Screening colonoscopy has been shown to reduce mortality and cancer stage in hereditary nonpolyposis colorectal cancer (HNPCC) individuals. However, the benefit of screening in intermediate risk groups is unknown. The most recent national guidelines have recommended a reduction of screening frequency for the intermediate risk group. Therefore, this study aims to compare the results of colonoscopic screening in HNPCC and intermediate risk groups and assess the effect of the most recent screening protocol recommendations. Method, A total of 244 individuals; 108 from HNPCC families (28 mismatch repair gene carriers) and 136 from intermediate risk families were referred for regular colonoscopic screening by the Regional Genetics Service. Findings from 417 colonoscopies performed between 1992 and 2003 were evaluated. Results, A total of three cancers, 39 adenomas and 41 hyperplastic polyps were found in the HNPCC group compared with one cancer, 22 adenomas and 19 hyperplasic polyps in the intermediate risk group. If the recent screening guidelines for the intermediate group were applied, then 89 (44%) fewer colonoscopies would have been performed. Although no cancers would have been missed, six adenomas (mean size = 5.7 mm, range 2,10 mm) with two graded as severely dysplasic and six hyperplastic polyps would not have been detected. Conclusion, The detection rate and distribution of adenomas were similar in both groups. If the new colonoscopic screening recommendations for the intermediate risk group had been applied, a small number of significant lesions would have been missed. [source] Malignant melanoma in patients with hereditary nonpolyposis colorectal cancerBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2008G. Ponti Summary Background, Malignant melanoma (MM) is the most aggressive skin cancer. Most MMs are sporadic, and in this setting an association with mismatch repair (MMR) gene mutations, typical of hereditary nonpolyposis colorectal cancer (HNPCC) tumours, has been proposed. Objectives, To characterize clinically and/or by molecular biology the patients with MM belonging to a cohort of 60 kindreds with HNPCC. Methods, Patients with HNPCC with a diagnosis of MM were studied by immunohistochemistry (IHC) on tumour tissue using antibodies to MLH1, MSH2, p16, ,-catenin and E-cadherin, and by direct sequencing of MMR genes on germline DNA, and BRAF and NRAS on somatic DNA extracted from MM. Results, Nine cutaneous MMs were detected in the tumour spectrum of eight families with HNPCC. The median age at diagnosis was 46 years. In one HNPCC family the diagnosis of MM was made in two first-degree relatives fitting the clinical definition of familial melanoma. IHC and sequencing analysis showed an MSH2 mutation in one patient with MM. Conclusions, Dermatological surveillance should be recommended to families in which MM is diagnosed in at least one member, especially at a young age. The combination of MMR gene mutations and abnormalities of p16 or other molecular pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM. [source] | |||||||||||||