title: MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study.
abstract: The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.
authors.affiliation: Hereditary Cancer Progam, Institut Català d'Oncologia, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Gausachs
authors.forename: Pilar
authors.initials: P
authors.lastname: Mur
authors.forename: Julieta
authors.initials: J
authors.lastname: Corral
authors.forename: Marta
authors.initials: M
authors.lastname: Pineda
authors.forename: Sara
authors.initials: S
authors.lastname: González
authors.forename: Llúcia
authors.initials: L
authors.lastname: Benito
authors.forename: Mireia
authors.initials: M
authors.lastname: Menéndez
authors.forename: Josep Alfons
authors.initials: JA
authors.lastname: Espinàs
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Iniesta
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000465:Algorithms; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics; D003362:Cost-Benefit Analysis; D019175:DNA Methylation; D005820:Genetic Testing / Q000191:economics* / Q000379:methods; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000191:economics / Q000379:methods; D055815:Young Adult
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