Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet

Ruhr-Universität Bochum, Bochum, North Rhine-Westphalia, Germany
Journal of Medical Genetics (Impact Factor: 6.34). 07/2007; 44(6):353-62. DOI: 10.1136/jmg.2007.048991
Source: PubMed


Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.

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    • "The Amsterdam II criteria (Vasen et al. 1999) and the revised Bethesda guidelines (Umar et al. 2004) have been used as triage methods based on clinical data. The sensitivity of the Amsterdam II criteria is low due to its highly strict requirements, and the evaluation of its specificity is divided (Syngal et al. 2000; Lipton et al. 2004; Vasen et al. 2007). The revised Bethesda guidelines have a sensitivity of 82-94% in patients with CRC (Syngal et al. 2000; Piñol et al. 2005), but their utility in other associated cancers is unknown. "
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    ABSTRACT: Lynch syndrome (LS) is an inherited disorder caused by a germline mutation in the DNA mismatch repair (MMR) genes and is associated with increased risk of various cancers, particularly colorectal cancer and endometrial cancer (EC). It is significant to identify LS in EC patients for prediction and prevention of the succeeding other associated cancers. However, useful LS screening guidelines for EC have not been established. The purpose of our study is to devise an efficient and practical screening strategy for LS in EC. We designed original criteria, named "APF criteria," with lenient terms (Age of onset < 50, or Personal or Family history of associated cancers) and applied it to unselected EC patients. We performed immunohistochemistry (IHC) and the methylation assay of MutL homolog 1 (MLH1) gene promoter using the tumors of patients who met our criteria, and thus selected "suspected LS" as the candidates for genetic analyses. Of 360 EC patients, 187 (51.9%) met the APF criteria, and the tumor specimens were available from 182 out of the 187 patients. IHC revealed that expression of at least one MMR protein was absent in cell nuclei of 54 (29.6%) tumors. Of 20 tumors lacking MLH1 protein expression, 14 cases were judged sporadic EC because of the hypermethylated MLH1 promoter. We thus selected 40 (11.1%) of 360 EC patients as "suspected LS." Our strategy that consists of clinical triage and the molecular analyses is expected to improve the screening efficiency and reduce the cost of LS identification in EC.
    Preview · Article · Feb 2015 · The Tohoku Journal of Experimental Medicine
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    • "Screening guidelines recommend colonoscopy screening for those older than 50 years [4]. All participating respondents therefore were 50 years or older and a US resident. "
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    ABSTRACT: The value of the information that genetic testing services provide can be questioned for insurance-based health systems. The results of genetic tests oftentimes may not lead to well-defined clinical interventions; however, Lynch syndrome, a genetic mutation for which carriers are at an increased risk for colorectal cancer, can be identified through genetic testing, and meaningful health interventions are available via increased colonoscopic surveillance. Valuations of test information for such conditions ought to account for the full impact of interventions and contingent outcomes. To conduct a discrete-choice experiment to elicit individuals' preferences for genetic test information. A Web-enabled discrete-choice experiment survey was administered to a representative sample of US residents aged 50 years and older. In addition to specifying expenditures on colonoscopies, respondents were asked to make a series of nine selections between two hypothetical genetic tests or a no-test option under the premise that a relative had Lynch syndrome. The hypothetical genetic tests were defined by the probability of developing colorectal cancer, the probability of a false-negative test result, privacy of the result, and out-of-pocket cost. A model specification identifying necessary interactions was derived from assumptions of risk behavior and the decision context and was estimated using random-parameters logit. A total of 650 respondents were contacted, and 385 completed the survey. The monetary equivalent of test information was approximately $1800. Expenditures on colonoscopies to reduce mortality risks affected valuations. Respondents with lower income or who reported being employed significantly valued genetic tests more. Genetic testing may confer benefits through the impact of subsequent interventions on private individuals. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Value in Health
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    • "Surveillance with upper endoscopy is offered to all Lynch syndrome patients every 2 years, starting from the age of 30–35 years. Annual renal ultrasound, urinalysis and urine cytology can be considered in families with a history of urinary tract tumors [58]. "
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    ABSTRACT: Although multimodal treatment has brought important benefit, there is still great heterogeneity regarding the indication and response to chemotherapy in Stage II and III, and individual variations related to both overall survival and toxicity of new therapies in metastatic disease or tumor relapse. Recent research in molecular biology led to the development of a large scale of genetic biomarkers, but their clinical use is not concordant with the high expectations. The Aim of this review is to identify and discuss the molecular markers with proven clinical applicability as prognostic and/or predictive factors in CRC and also to establish a feasible algorithm of molecular testing, as routine practice, in the personalized, multidisciplinary approach of colorectal cancer patients in our country. Despite the revolu¬tion that occurred in the field of molecular marker research, only Serum CEA, Immunohistochemical analysis of mismatch repair proteins and PCR testing for KRAS and BRAF mutations have confirmed their clinical utility in the management of colorectal cancer. Their implementation in the current practice should partially resolve some of the controversies related to this heterogenic pathology, in matters of prognosis in different TNM stages, stage II patient risk stratification, diagnosis of hereditary CRC and likelihood of benefit from anti EGFR therapy in metastatic disease. The proposed algorithms of molecular testing are very useful but still imperfect and require further validation and constant optimization.
    Full-text · Article · Mar 2014 · Journal of medicine and life
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