title: Evaluation of predictive models in daily practice for the identification of patients with Lynch syndrome.
abstract: The optimal strategy for identifying patients with Lynch syndrome among patients with newly diagnosed colorectal cancer (CRC) is still debated. Several predictive models (e.g., MMRpredict, PREMM1,2 and MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome-causing mutation. Their clinical applicability to patients with CRC from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and compared to the revised Bethesda guidelines and a molecular strategy based on MSI testing in all patients followed by the exclusion of MSI-positive sporadic cases from mutational testing by screening for BRAF mutation and MLH1 promoter methylation. The sensitivities of the three models, at the lowest thresholds proposed, were identical (75%), with similar numbers of probands eligible for further MSI testing (almost half the patients). In our dataset, the prediction models gave no better discrimination than the revised Bethesda guidelines. Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all patients with Lynch syndrome in our series of consecutive CRC. Our results support systematic screening for MMR deficiency in all new CRC cases.
authors.affiliation: AP-HP, Fédération des Spécialités Digestives, Hôpital Ambroise Paré, Université Versailles-Saint Quentin en Yvelines, Boulogne, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tresallet
authors.forename: Antoine
authors.initials: A
authors.lastname: Brouquet
authors.forename: Catherine
authors.initials: C
authors.lastname: Julié
authors.forename: Alain
authors.initials: A
authors.lastname: Beauchet
authors.forename: Céline
authors.initials: C
authors.lastname: Vallot
authors.forename: Fabrice
authors.initials: F
authors.lastname: Ménégaux
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mitry
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.forename: Robert
authors.initials: R
authors.lastname: Malafosse
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.forename: Bernard
authors.initials: B
authors.lastname: Nordlinger
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.forename: Christine
authors.initials: C
authors.lastname: Muti
authors.forename: Christophe
authors.initials: C
authors.lastname: Penna
authors.forename: Hélène
authors.initials: H
authors.lastname: Hofmann-Radvanyi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1