The tumor spectrum in the Lynch syndrome.
ABSTRACT Colorectal and endometrial cancer are the characteristic tumors of the Lynch syndrome. We reviewed the available evidence on the occurrence of other types of cancer in the syndrome, aiming to identify those types that can be included in the tumor spectrum, based on this evidence. We chose to define the tumor spectrum as comprising the cancers for which Lynch syndrome patients are at elevated risk. We found sufficiently strong and consistent evidence to include gastric cancer, small bowel cancer, hepatobiliary tract cancer, upper urologic tract cancer, ovarian cancer, and brain tumors in this spectrum, in addition to colorectal and endometrial cancer. We predict that the spectrum will expand as additional studies are reported, especially as prospective studies of mutation carriers are completed.
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ABSTRACT: Lynch syndrome is associated with germline mutations in DNA mismatch repair (MMR) genes. Up to 30% of DNA changes found are variants of unknown significance (VUS). Our aim was to assess the pathogenicity of eight MLH1 VUS identified in patients suspected of Lynch syndrome. All of them are novel or not previously characterized. For their classification, we followed a strategy that integrates family history, tumor pathology, and control frequency data with a variety of in silico and in vitro analyses at RNA and protein level, such as MMR assay, MLH1 and PMS2 expression, and subcellular localization. Five MLH1 VUS were classified as pathogenic: c.[248G>T(;)306G>C], c.[780C>G;788A>C], and c.791-7T>A affected mRNA processing, whereas c.218T>C (p.L73P) and c.244G>A (p.T82A) impaired MMR activity. Two other VUS were considered likely neutral: the silent c.702G>A variant did not affect mRNA processing or stability, and c.974G>A (p.R325Q) did not influence MMR function. In contrast, variant c.25C>T (p.R9W) could not be classified, as it associated with intermediate levels of MMR activity. Comprehensive functional assessment of MLH1 variants was useful in their classification and became relevant in the diagnosis and genetic counseling of carrier families. Hum Mutat 33:1576-1588, 2012. © 2012 Wiley Periodicals, Inc.Human Mutation 01/2013; 33(11):1576-88. DOI:10.1002/humu.22142 · 5.05 Impact Factor
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ABSTRACT: AimInfertility is a concern for young colorectal cancer (CRC) survivors, but this risk is not well quantified. Mismatch repair (MMR) mutation carriers are a useful cohort for studying fertility after CRC as they commonly develop CRC when young, and unaffected family members provide demographically similar controls. The aim of this study was to determine the effect of CRC on fertility in a large cohort of MMR mutation carriers.MethodMMR mutation carriers identified from the Australasian Colorectal Cancer Family Registry were included. For each year of life within the fertile age range (15 to 49), the number of livingindividuals and the number of children born to them were determined.Individuals were grouped by whether or not they had had a diagnosis of CRC by that age. Age- specific and total fertility rates were calculated.Results1068 subjects (611 women and 457 men) were identified, of whom 467 were diagnosed with CRC. There were 1,192 births during 18674 person- years of follow up of the women and 814 births during 14013 person- years of follow up to the men.The total fertility rate was decreased in women after a diagnosis of CRC compared who did not have CRC (1.3 vs. 2.2 P=0.0011), but age- specific fertility was only reduced in the 20-24 year age group. In men TFR was similar for both groups (2.0 vs. 1.8) P = 0.27).Conclusion Age- specific fertility was decreased in female CRC survivors with Lynch syndrome aged 20-24, but not in older women or in men.This article is protected by copyright. All rights reserved.Colorectal Disease 03/2015; DOI:10.1111/codi.12940 · 2.02 Impact Factor
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ABSTRACT: Background: Gall stone disease is one of the commonly handled surgical pathologies by a General Surgeon. Major intra operative complications are less commonly encountered in experienced hands. The rate may increase in a teaching hospital where Residents are allowed to operate. Therefore it was with this assumption that a study was carried to assess the incidence and contributing factors for the complications in a tertiary teaching hospital. Methods: A retrospective chart and operation log book review was done in a two -year period between January 2009 and December 2010 in St Paul’s teaching hospital, AA, Ethiopia. Results: A total of 645 cholecystectomy, 588(91.2%) open and 57(8.8%) laparoscopic, were done in the study period. Females comprised 80.9% of the patients. The average age of the patients was 42.8 years with a range of 18 to 80. Major surgical complications were seen in 19(2.9%) patients but adequate information was found for 16 patients only with a retrieval rate of 84.2 %. Of the 16 patients 14(87.5%) were female. Thirteen patients had open cholecystectomy and the rest 3 patients had laparoscopic cholecystectomy. Accordingly the rate for open cholecystectomy was 13/588(2.21%), and that of laparoscopic surgery 3/57(5.26%). Twelve (92.3%) of the complicated cases in open cholecystectomy were done by residents alone. The rate of complications for the consultants in open surgery was 0.2% and that of the residents 6.0%. The odd that patients operated by residents will develop IBDI was 6.25 times higher than that of the seniors. There is statistically significant association between seniority and major surgical complications(X2= 11.91, P=0.001). Conclusions: The incidence of major complications of cholecystectomy is unacceptably high in this study. Almost all complications occurred in the hands of residents which show that experience matters. Therefore it is our recommendation that residents should not be left alone until they get reasonable experience in the field.