Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents

Bodo, S.; Colas, C.; Buhard, O.; Collura, A.; Tinat, J.; Lavoine, N.; Guilloux, A.; Chalastanis, A.; Lafitte, P.; Coulet, F.; Buisine, M. P.; Ilencikova, D.; Ruiz Ponte, Clara; 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, U. J.; Soubrier, F.; Mortemousque, I.; Leis, A.; Auclair-Perrossier, J.; Frébourg, T.; Fléjou, J. F.; Entz-Werle, N.; Leclerc, J.; Malka, D.; Cohen-Haguenauer, O.; Goldberg, Y.; Gerdes, A. M.; Fedhila, F.; Mathieu-Dramard, M.; Hamelin, R.; Wafaa, B.; Gauthier-Villars, M.; Bourdeaut, F.; Sheridan, E.; Vasen, H.; Brugières, L.; Wimmer, K.; Muleris, M.; Duval, A.
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Date issued
2015
Journal title
Gastroenterology
Type of content
Artigo
MeSH
Adaptor Proteins, Signal Transducing | Adenosine Triphosphatases | Adult | Antineoplastic Agents, Alkylating | Biomarkers, Tumor | Brain Neoplasms | Caco-2 Cells | Case-Control Studies | Colorectal Neoplasms | Colorectal Neoplasms, Hereditary Nonpolyposis | DNA Mutational Analysis | DNA Repair Enzymes | DNA-Binding Proteins | Drug Resistance, Neoplasm | Female | Genetic Predisposition to Disease | Genetic Testing | Germ-Line Mutation | HCT116 Cells | Heredity | Humans | Lymphocytes | Male | Methylation | Microsatellite Instability | Mismatch Repair Endonuclease PMS2 | Multiplex Polymerase Chain Reaction | MutL Protein Homolog 1 | MutS Homolog 2 Protein | Neoplastic Syndromes, Hereditary | Nuclear Proteins | Phenotype | Predictive Value of Tests | Reproducibility of Results | Transfection | Young Adult | Colon Cancer | Functional Tests | Predisposition | Tumor
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.