RESUMEN
Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is the most common known genetic syndrome for colorectal cancer (CRC). MLH1/MSH2 mutations underlie approximately 90% of Lynch syndrome families. A total of 24% of these mutations are missense. Interpreting missense variation is extremely challenging. We have therefore developed multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR), a bioinformatic algorithm that effectively classifies MLH1/MSH2 deleterious and neutral missense variants. We compiled a large database (n>300) of MLH1/MSH2 missense variants with associated clinical and molecular characteristics. We divided this database into nonoverlapping training and validation sets and tested MAPP-MMR. MAPP-MMR significantly outperformed other missense variant classification algorithms (sensitivity, 94%; specificity, 96%; positive predictive value [PPV] 98%; negative predictive value [NPV], 89%), such as SIFT and PolyPhen. MAPP-MMR is an effective bioinformatic tool for missense variant interpretation that accurately distinguishes MLH1/MSH2 deleterious variants from neutral variants.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Bases de Datos Genéticas , Proteína 2 Homóloga a MutS/genética , Mutación Missense , Proteínas Nucleares/genética , Reparación de la Incompatibilidad de ADN , Femenino , Humanos , Masculino , Inestabilidad de Microsatélites , Análisis Multivariante , Homólogo 1 de la Proteína MutLRESUMEN
Human genetic variation data is now publicly available on a large scale, from both public and private discovery efforts. Datasets from the International Haplotype Map Consortium and Perlegen Sciences provide a level of knowledge about human genetic variation that is unprecedented. In combination with novel high-throughput genotyping technologies, these new resources will allow cancer prevention investigators to identify in a more precise way which genetic subsets of patients are likely to benefit most from chemoprevention and screening interventions.
Asunto(s)
Quimioprevención , Pruebas Genéticas/tendencias , Neoplasias/genética , Neoplasias/prevención & control , Ensayos Clínicos como Asunto , Predisposición Genética a la Enfermedad , Técnicas Genéticas , Pruebas Genéticas/métodos , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Human genetic variation data are now publicly available on a large scale, from public and private discovery efforts. Datasets from the International Haplotype Map Consortium and Perlegen Sciences provide a level of knowledge about human genetic variation that is unprecedented. In combination with novel high-throughput genotyping technologies, these new resources will allow cancer prevention investigators to identify in a more precise way which genetic subsets of patients are likely to benefit most from chemoprevention and screening interventions.