1. Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents.
- Author
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Bodo S, Colas C, Buhard O, Collura A, Tinat J, Lavoine N, Guilloux A, Chalastanis A, Lafitte P, Coulet F, Buisine MP, Ilencikova D, Ruiz-Ponte C, Kinzel M, Grandjouan S, Brems H, Lejeune S, Blanché H, Wang Q, Caron O, Cabaret O, Svrcek M, Vidaud D, Parfait B, Verloes A, Knappe UJ, Soubrier F, Mortemousque I, Leis A, Auclair-Perrossier J, Frébourg T, Fléjou JF, Entz-Werle N, Leclerc J, Malka D, Cohen-Haguenauer O, Goldberg Y, Gerdes AM, Fedhila F, Mathieu-Dramard M, Hamelin R, Wafaa B, Gauthier-Villars M, Bourdeaut F, Sheridan E, Vasen H, Brugières L, Wimmer K, Muleris M, and Duval A
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adenosine Triphosphatases genetics, Adult, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Caco-2 Cells, Case-Control Studies, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, 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 genetics, DNA-Binding Proteins genetics, Female, Genetic Predisposition to Disease, HCT116 Cells, Heredity, Humans, Lymphocytes metabolism, Male, Methylation, Mismatch Repair Endonuclease PMS2, Multiplex Polymerase Chain Reaction, MutL Protein Homolog 1, MutS Homolog 2 Protein genetics, Neoplastic Syndromes, Hereditary drug therapy, Neoplastic Syndromes, Hereditary genetics, Neoplastic Syndromes, Hereditary metabolism, Neoplastic Syndromes, Hereditary pathology, Nuclear Proteins genetics, Phenotype, Predictive Value of Tests, Reproducibility of Results, Transfection, Young Adult, Antineoplastic Agents, Alkylating therapeutic use, Biomarkers, Tumor genetics, Brain Neoplasms diagnosis, Colorectal Neoplasms diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Drug Resistance, Neoplasm, Genetic Testing methods, Germ-Line Mutation, Lymphocytes drug effects, Microsatellite Instability, Neoplastic Syndromes, Hereditary diagnosis
- Abstract
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., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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