Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Gastroenterology & Hepatology, Colon Cancer, Functional Tests, Predisposition, Tumor, NEUROFIBROMATOSIS TYPE-1, COLORECTAL-CANCER, BIALLELIC MUTATIONS, SOMATIC MUTATIONS, MSH6 MUTATIONS, GOLD STANDARD, PMS2, CELLS, HEREDITARY, SYSTEM, 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, European Consortium “Care for CMMRD”, 1103 Clinical Sciences, 1109 Neurosciences, 1114 Paediatrics and Reproductive Medicine, 3202 Clinical sciences, 3210 Nutrition and dietetics

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 non-informative 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.