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Medline ® Abstracts for References 42,47-51

of 'Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis'

42
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Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer.
AU
Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK
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Dis Colon Rectum. 2014;57(8):1025.
 
The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; -6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; provides guidelines for screening at-risk and affected persons with Lynch syndrome; and lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.
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1Johns Hopkins University School of Medicine, Baltimore, Maryland 2Yale University School of Medicine, New Haven, Connecticut 3Baylor University Medical Center at Dallas, Texas 4Cleveland Clinic, Cleveland, Ohio 5University of Utah, Salt Lake City, Utah 6VA Puget Sound Health Care System, Seattle, Washington 7University of Washington, Seattle, Washington 8Eastern Virginia Medical School, Norfolk, Virginia 9Stanford University, Palo Alto, California 10Kaiser Permanente Medical Center, Walnut Creek, California 11Oregon Health and Science University, Portland, Oregon 12White River Junction VA Medical Center, White River Junction, Vermont 13Geisel School of Medicine at Dartmouth, White River Junction, Vermont 14Brigham and Women's Hospital, Boston, Massachusetts 15Dana Farber Cancer Institute, Boston, Massachusetts 16Harvard Medical School, Boston, Massachusetts 17Indiana University School of Medicine, Indianapolis, Indiana.
PMID
47
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Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).
AU
Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior TW, Westman J, Panescu J, Fix D, Lockman J, Comeras I, de la Chapelle A
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N Engl J Med. 2005;352(18):1851.
 
BACKGROUND: Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome.
METHODS: Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing.
RESULTS: Of1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not.
CONCLUSIONS: Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.
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Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, USA.
PMID
48
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The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.
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Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, Halling KC, McDonnell SK, Schaid DJ, Walsh Vockley C, Kubly V, Nelson H, Michels VV, Thibodeau SN
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Am J Hum Genet. 2001;69(4):780. Epub 2001 Aug 24.
 
A comprehensive analysis of somatic and germline mutations related to DNA mismatch-repair (MMR) genes can clarify the prevalence and mechanism of inactivation in colorectal carcinoma (CRC). In the present study, 257 unselected patients referred for CRC resection were examined for evidence of defective DNA MMR. In particular, we sought to determine the frequency of hereditary defects in DNA MMR in this cohort of patients. MMR status was assessed by testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 patients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (n=48) or hMSH2 (n=3). All three patients lacking hMSH2, as well as one patient lacking hMLH1, also demonstrated an absence of hMSH6. DNA sequence analysis of the 51 patients with defective MMR revealed seven germline mutations-four in hMLH1 (two truncating and two missense) and three in hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients with germline mutations, only three had family histories consistent with hereditary nonpolyposis colorectal cancer. Of the remaining patients who hadtumors with defective MMR, eight had somatic mutations in hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that showed loss of hMLH1 expression but no detectable hMLH1 mutations. Our results suggest that, although defective DNA MMR occurs in approximately 20% of unselected patients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 patients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defects in MMR. The epigenetic (nonhereditary) mechanism of hMLH1 promoter hypermethylation appears to be responsible for the majority of the remaining patients whose tumors are characterized by defective DNA MMR.
AD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
PMID
49
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Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study.
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Percesepe A, Borghi F, Menigatti M, Losi L, Foroni M, Di Gregorio C, Rossi G, Pedroni M, Sala E, Vaccina F, Roncucci L, Benatti P, Viel A, Genuardi M, Marra G, Kristo P, Peltomäki P, Ponz de Leon M
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J Clin Oncol. 2001;19(19):3944.
 
PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer.
PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1.
RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P<.01), high mucinous component (P<.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations.
CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%]of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.
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Department of Internal Medicine, University of Modena, Modena, Italy. percesepe.antonio@unimo.it
PMID
50
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Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population.
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Ravnik-Glavac M, Potocnik U, Glavac D
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J Med Genet. 2000;37(7):533.
 
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PMID
51
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Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening.
AU
JuliéC, Trésallet C, Brouquet A, Vallot C, Zimmermann U, Mitry E, Radvanyi F, Rouleau E, Lidereau R, Coulet F, Olschwang S, Frébourg T, Rougier P, Nordlinger B, Laurent-Puig P, Penna C, Boileau C, Franc B, Muti C, Hofmann-Radvanyi H
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Am J Gastroenterol. 2008;103(11):2825.
 
BACKGROUND: The identification of individuals who should undergo hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing remains a critical issue. The Bethesda guidelines were developed to preselect patients for microsatellite instability (MSI) testing before germline mutation screening. These criteria have been revised, and a new set of recommendations, the revised Bethesda guidelines, has been proposed.
OBJECTIVE: To evaluate the performance of these revised guidelines for identifying patients with HNPCC in a series of unselected consecutive patients and compare this revised guidelines-based approach with a molecular strategy (MSI testing for all tumors, followed by exclusion of MSI-positive sporadic cases from mutational testing).
PATIENTS AND METHODS: The study included 214patients with newly diagnosed colorectal cancer. The MSI analysis was performed for all tumors. Germline testing, guided by immunohistochemical staining for mismatch repair proteins, was performed for patients with MSI-positive tumors. Sporadic MSI-positive tumors were identified by screening for BRAF mutation and MLH1 promoter methylation.
RESULTS: Ninety patients (42.1%) met the revised guidelines. Twenty-one patients (9.8%) had MSI-positive tumors. Germline testing identified eight mutations (3.7%) (MSH2 N = 5, MLH1 N = 2, MSH6 N =1). The revised guidelines failed to identify 2 of the 8 probands (aged 67 and 81 yr, both with no family history). In contrast, the molecular strategy identified all patients requiring testing for germline mutation. The percentages of patients selected for germline testing by the revised guidelines and the molecular strategy were 4.2% and 5.1%, respectively.
CONCLUSIONS: The revised Bethesda guidelines did not identify all HNPCC cases in our series. The molecular approach identified all HNPCC patients with MSI-positive tumors, increasing the workload for germline testing only slightly.
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Service d'Anatomie et de Cytologie Pathologiques, Hôpital Ambroise Paré, AP-HP, UniversitéVersailles-Saint Quentin en Yvelines, Boulogne, France.
PMID