Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents
Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain...
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| Published in | Gastroenterology Vol. 149; no. 4; pp. 1017 - 1029.e3 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.10.2015
Elsevier BV |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0016-5085 1528-0012 1528-0012 |
| DOI | 10.1053/j.gastro.2015.06.013 |
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| Abstract | Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD.
We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD.
In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features.
The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients. |
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| AbstractList | Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD.
We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD.
In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features.
The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients. Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD.BACKGROUND & AIMSPatients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD.We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD.METHODSWe examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD.In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features.RESULTSIn the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features.The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.CONCLUSIONThe presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients. Background & Aims Patients with bi-allelic germline mutations in mismatch repair (MMR) genes ( MLH1 , MSH2 , MSH6 , or PMS2 ) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. Methods We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. Results In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. Conclusion The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients. |
| Author | Malka, David Sheridan, Eamonn Knappe, Ulrich J. Chalastanis, Alexandra Lafitte, Philippe Wang, Qing Verloes, Alain Wafaa, Badre Mathieu-Dramard, Michèle Cabaret, Odile Cohen-Haguenauer, Odile Gerdes, Anne-Marie Soubrier, Florent Lejeune, Sophie Bodo, Sahra Buhard, Olivier Vidaud, Dominique Vasen, Hans Wimmer, Katharina Muleris, Martine Gauthier-Villars, Marion Lavoine, Noémie Guilloux, Agathe Mortemousque, Isabelle Bourdeaut, Franck Frébourg, Thierry Brems, Hilde Collura, Ada Caron, Olivier Buisine, Marie-Pierre Leclerc, Julie Duval, Alex Svrcek, Magali Tinat, Julie Grandjouan, Sophie Goldberg, Yael Fedhila, Faten Ruiz-Ponte, Clara Leis, Alexander Colas, Chrystelle Ilencikova, Denisa Fléjou, Jean-François Brugières, Laurence Coulet, Florence Auclair-Perrossier, Jessie Hamelin, Richard Blanché, Hélène Parfait, Béatrice Entz-Werle, Natacha Kinzel, Miriam |
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| BackLink | https://cir.nii.ac.jp/crid/1873679867570338048$$DView record in CiNii https://www.ncbi.nlm.nih.gov/pubmed/26116798$$D View this record in MEDLINE/PubMed https://univoak.hal.science/hal-05267916$$DView record in HAL |
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| Copyright | 2015 AGA Institute AGA Institute Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved. Distributed under a Creative Commons Attribution 4.0 International License |
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| DOI | 10.1053/j.gastro.2015.06.013 |
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| Keywords | CMMRD MSI IHC LS Functional Tests 6-TG gMSI MMR evMSI FAP LCL VUS Colon Cancer Predisposition NF1 Tumor PBLs MNNG microsatellite instability ex vivo microsatellite instability mismatch repair lymphoblastoid cell line immunohistochemistry Lynch syndrome variant of unknown functional significance germline microsatellite instability peripheral blood lymphocytes constitutional mismatch repair 6-thioguanine N-methyl- N-nitro- N-nitrosoguanidine neurofibromatosis type 1 familial adenomatous polyposis |
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| Snippet | Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome... Background & Aims Patients with bi-allelic germline mutations in mismatch repair (MMR) genes ( MLH1 , MSH2 , MSH6 , or PMS2 ) develop a rare but severe variant... BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of... |
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| SubjectTerms | Adaptor Proteins Adaptor Proteins, Signal Transducing Adaptor Proteins, Signal Transducing - genetics Adenosine Triphosphatases Adenosine Triphosphatases - genetics Adult Alkylating Antineoplastic Agents Antineoplastic Agents, Alkylating Antineoplastic Agents, Alkylating - therapeutic use Biomarkers Biomarkers, Tumor Biomarkers, Tumor - genetics Brain Neoplasms Brain Neoplasms - diagnosis Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Caco-2 Cells Case-Control Studies Colon Cancer Colorectal Neoplasms Colorectal Neoplasms - diagnosis Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Colorectal Neoplasms, Hereditary Nonpolyposis Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis Colorectal Neoplasms, Hereditary Nonpolyposis - drug therapy Colorectal Neoplasms, Hereditary Nonpolyposis - genetics Colorectal Neoplasms, Hereditary Nonpolyposis - metabolism Colorectal Neoplasms, Hereditary Nonpolyposis - pathology DNA Mutational Analysis DNA Repair Enzymes DNA Repair Enzymes - genetics DNA-Binding Proteins DNA-Binding Proteins - genetics Drug Resistance Drug Resistance, Neoplasm Female Functional Tests Gastroenterology and Hepatology Genetic Predisposition to Disease Genetic Testing Genetic Testing - methods Germ-Line Mutation HCT116 Cells Hereditary Hereditary Nonpolyposis Heredity Humans Lymphocytes Lymphocytes - drug effects Lymphocytes - metabolism Male Methylation Microsatellite Instability Mismatch Repair Endonuclease PMS2 Multiplex Polymerase Chain Reaction MutL Protein Homolog 1 MutS Homolog 2 Protein MutS Homolog 2 Protein - genetics Neoplasm Neoplastic Syndromes Neoplastic Syndromes, Hereditary Neoplastic Syndromes, Hereditary - diagnosis Neoplastic Syndromes, Hereditary - drug therapy Neoplastic Syndromes, Hereditary - genetics Neoplastic Syndromes, Hereditary - metabolism Neoplastic Syndromes, Hereditary - pathology Nuclear Proteins Nuclear Proteins - genetics Phenotype Predictive Value of Tests Predisposition Reproducibility of Results Signal Transducing Transfection Tumor Young Adult |
| Title | Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents |
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