scholarly journals Clinical, anamnestic, molecular and genetic criteria for Lynch syndrome

2019 ◽  
Vol 6 (4) ◽  
pp. 38-46
Author(s):  
A. V. Semyanikhina ◽  
N. I. Pospekhova ◽  
M. G. Filippova ◽  
D. A. Golovina ◽  
A. O. Rasulov ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Expression Patterns ◽  
Clinical Criteria ◽  
Mmr Genes ◽  
Leading Role ◽  
Amsterdam Criteria ◽  
Colorectal Cancer Patients ◽  
Mmr Proteins

Lynch syndrome is the most common cancer-prone syndrome associated with a high risk of colorectal cancer (CRC), neoplasms of the upper gastrointestinal system, the urinary tract, the female reproductive system, brain tumours and others. The only known form of hereditary endometrial cancer is also diagnosed as part of Lynch syndrome. One or more pathogenic germline mutations in one of the mismatch repair (MMR) genes are the cause of Lynch syndrome. Mapping of MMR genes and the discovery of microsatellite instability (MSI) have given rise to the possibility of using these clue characteristics of the pathogenic process for the elaboration of a screening test for Lynch syndrome. Being highly accurate and superior to all previously developed clinical criteria and guidelines, MSI-testing along with the assessment of the expression patterns of MMR proteins by immunohistochemistry has taken the leading role in the early diagnosis of Lynch syndrome. This article focuses on a brief review about the main evolutionary stages of clinical, anamnestic, molecular and genetic criteria for Lynch syndrome together with the results of our own research on the accuracy of the Amsterdam criteria, the Bethesda guidelines and MSI-diagnostics in the determination of the indications for MMR-genotyping in colorectal cancer patients suspected for Lynch syndrome.

scholarly journals Lynch syndrome I: A case report

2008 ◽  
Vol 61 (1-2) ◽  
pp. 79-82
Author(s):  
Vesna Zivkovic ◽  
Vuka Katic ◽  
Jasmina Gligorijevic ◽  
Zlatibor Andjelkovic ◽  
Aleksandar Petrovic ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Report ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Clinical Stage ◽  
Family Members ◽  
Advanced Rectal Cancer ◽  
Degree Relative ◽  
Mmr Genes ◽  
Amsterdam Criteria

Introduction. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndromes J and II, accounts for about 5-8% of colorectal cancers. Lynch syndrome I is an autosomal domi?nant inherited disorder characterized by early onset of colorectal cancer, predominance of proximal and multiple tumors, and microsatellite instability. In order to identify HNPCC, the international "Amsterdam criteria" have been used. Case report. The proband was a 40-year-old male who was admitted to hospital with a diagnosis of advanced rectal cancer. Left colectomy was carried out. A histopathologic diagnosis of poorly differentiated adenocarcinoma of clinical stage Dukes C was made. The family talking was done and it was revealed that the pro-band had five family members (one of first degree relative) with colorectal cancer, and two successive generations affected. All malignancy were diagnosed before 45 years of age. In one family member, metachronous transverse cancer was revealed 12 years after surgery for cecal adenocarcinoma. Discussion and conclusion. The main molecular cause for HNPCC is constitutional mutation in one of the mismatch repair (MMR) genes that regulate the excision of errors occurring during DNA replication. The most often are mutations of MLHI and MSH2 genes, and microsatellite instability is present in about 90-95% HNPCC. In this report, we present a case of an HNPCC patient who met the Amsterdam criteria for Lynch syndrome I. Family members that fulfill the Amsterdam criteria should be investigated for mutation in MMR genes. The genetic tests are not routinely available, so colonoscopic screening of all asymptomatic family members older than 25 has been recommended.

Use of Molecular Tumor Characteristics to Prioritize Mismatch Repair Gene Testing in Early-Onset Colorectal Cancer

2005 ◽  
Vol 23 (27) ◽  
pp. 6524-6532 ◽  
Author(s):  
Melissa C. Southey ◽  
Mark A. Jenkins ◽  
Leeanne Mead ◽  
Jonathan Whitty ◽  
Melanie Trivett ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Protein Expression ◽  
Cancer Patients ◽  
Gene Mutation ◽  
Early Onset ◽  
Amsterdam Criteria ◽  
Colorectal Cancer Patients ◽  
Early Onset Colorectal Cancer ◽  
Mmr Proteins

Purpose The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. Methods We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. Results Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. Conclusions Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation–carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

Determination of splice-site mutations in Lynch syndrome (hereditary non-polyposis colorectal cancer) patients using functional splicing assay

2009 ◽  
Vol 8 (4) ◽  
pp. 509-517 ◽  
Author(s):  
Hiromu Naruse ◽  
Noriko Ikawa ◽  
Kiyoshi Yamaguchi ◽  
Yusuke Nakamura ◽  
Masami Arai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Cancer Patients ◽  
Splice Site ◽  
Colorectal Cancer Patients

scholarly journals Diagnostic Application ofhMLH1Methylation in Hereditary Non-Polyposis Colorectal Cancer

2004 ◽  
Vol 20 (4-5) ◽  
pp. 277-282 ◽  
Author(s):  
Nagahide Matsubara
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Genetic Test ◽  
Screening Program ◽  
Immunohistochemical Analysis ◽  
Germline Mutations ◽  
Clinical Criteria ◽  
Pathological Analysis ◽  
Mmr Genes ◽  
New Strategy

Colorectal cancer (CRC) due to mismatch repair (MMR) defect has distinct characteristics among unselected CRCs. These CRCs are biologically less aggressive and, thus, showing better prognosis but less sensitive to the 5FU-based chemotherapy. CRCs with MMR defect derive from both hereditary and sporadic reasons. Germline inactivation of MMR genes (hMLH1, hMSH2, hMSH6, andhPMS2) underlies the hereditary CRC with MMR defect (Lynch syndrome) and epigenetic silencing ofhMLH1gene causes the sporadic CRC with MMR defect. Hereditary and sporadic CRC with MMR defect can be detectable by microsatellite instability (MSI) test or immunohistochemical analysis among general CRCs. Lynch syndrome can be diagnosed by the clinical criteria or by genetic test to detect pathogenic germline mutations in MMR genes. However, both clinical criteria and genetic test are inadequate for the diagnosis of Lynch syndrome. Since genetic test for the diagnosis of the Lynch syndrome is expensive and not always identify pathogenic germline mutations, effective and inexpensive screening program is desirable. Here we propose a possible application of methylation test combined with MSI or pathological analysis as an effective and a cost-saving new strategy for screening of Lynch syndrome.

scholarly journals Cumulative risks of colorectal cancer in Han Chinese patients with Lynch syndrome in Taiwan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abram Bunya Kamiza ◽  
Wen-Chang Wang ◽  
Jeng-Fu You ◽  
Reiping Tang ◽  
Huei-Tzu Chien ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Cumulative Risk ◽  
Germline Mutations ◽  
Han Chinese ◽  
Chinese Patients ◽  
Mutation Carriers ◽  
Amsterdam Criteria ◽  
Cumulative Risks ◽  
Age And Sex

AbstractPatients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%–89.9%) and 76.7% (95% CI = 37.2%–99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%–57.7%) and 49.3% (95% CI = 21.9%–84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.

scholarly journals Performance of tumor testing for Lynch syndrome identification in patients with colorectal cancer: A retrospective single-center study

2018 ◽  
Vol 105 (1) ◽  
pp. 76-83 ◽  
Author(s):  
Stefano Signoroni ◽  
Maria Grazia Tibiletti ◽  
Maria Teresa Ricci ◽  
Massimo Milione ◽  
Federica Perrone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Characteristic Curve ◽  
Age At Onset ◽  
Area Under The Curve ◽  
Single Center ◽  
Germline Variants ◽  
Amsterdam Criteria ◽  
Clinicopathologic Parameters ◽  
Msi Analysis

Objective: To investigate the performance of tumor testing approaches in the identification of Lynch syndrome (LS) in a single-center cohort of people with colorectal cancer (CRC). Methods: A retrospective analysis of data stored in a dedicated database was carried out to identify patients with CRC suspected for LS who were referred to Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, between 1999 and 2014. The sensitivity and specificity of immunohistochemistry (IHC) for mismatch repair (MMR) proteins and microsatellite instability (MSI) analysis (alone or combined) were calculated with respect to the presence of causative MMR germline variants. Results: A total of 683 patients with CRC suspected for LS were identified. IHC results of MMR protein analysis and MSI were assessed in 593 and 525 CRCs, respectively, while germline analysis was performed in 418 patients based on the IHC or MSI test result and/or clinical features. Univariate and multivariate analysis revealed a significant correlation of pathogenic MMR germline variants with all clinicopathologic features including Amsterdam criteria, presence of endometrial cancer, CRC site, age at onset, stage, and grade. The highest odds ratio values were observed for IHC and MSI (17.1 and 8.8, respectively). The receiver operating characteristic curve and area under the curve values demonstrated that IHC alone or combined with other clinicopathologic parameters was an excellent test for LS identification. Conclusions: This study confirms the effectiveness of tumor testing to identify LS among patients with CRC. Although IHC and MSI analysis were similarly effective, IHC could be a better strategy for LS identification as it is less expensive and more feasible.

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