title: Validation microsatellite path score in a population-based cohort of patients with colorectal cancer.
abstract: OBJECTIVE
  Bethesda guidelines are used to recognize patients at risk for Lynch syndrome. However, obtaining personal and familial tumor data can sometimes be difficult. The Microsatellite Path Score (MsPath), a pathological score, based on age, tumor location, and pathologic features, has been developed to effectively predict colorectal cancer with DNA mismatch repair (MMR) deficiencies. However, the MsPath model's performance in an unselected, population-based colorectal cancer (CRC) population is unknown.
  
  
  METHODS
  We analyzed all patients with CRC regardless of age, personal or family history, and tumor characteristics from the EPICOLON study, an independent, prospective, multicenter, population-based cohort (N = 1,222). All patients underwent tumor microsatellite instability (MSI) analysis and immunostaining for MLH1/MSH2, and those with MMR underwent tumor BRAF mutation analysis and MLH1/MSH2 germline testing. All the pathologic features were centralized and evaluated blinded to the MMR status.
  
  
  RESULTS
  MsPath score for prediction of having MSI high, with the recommended MsPath cutoff score ≥1.0, had a sensitivity, specificity, and positive predictive value (PPV) of 92.8% (95% CI, 86.9 to 98.3), 64.1% (95% CI, 61.1 to 66.8), and 15.8% (95% CI, 12.2 to 18.6), respectively. MsPath score had a sensitivity, specificity, and PPV of 81.8% (95% CI, 59.0 to 99.8), 60.6% (95% CI, 57.8 to 63.4), and 1.9% (95% CI, 0.7 to 3.1), respectively, for the identification of MLH1/MSH2 gene carriers. Application of the MsPath score, resulted in two (18%) of 11 mutation carriers being missed, both pathogenic germline MSH2 mutations.
  
  
  CONCLUSIONS
  In the general nonselected population, the MsPath score accurately predicted the probability of bearing a MSI high CRC, but it was insufficiently accurate to use for the selection of patients warranting MLH1/MSH2 mutation testing in the setting of Lynch syndrome.
authors.affiliation: Hospital del Mar de Barcelona. Parc de Salut Mar. Passeig Marítim 25-29, 08003-Barcelona, Catalonia, Spain. xbessa@hospitaldelmar.cat
authors.forename: Xavier
authors.initials: X
authors.lastname: Bessa
authors.forename: Cristina
authors.initials: C
authors.lastname: Alenda
authors.forename: Artemio
authors.initials: A
authors.lastname: Paya
authors.forename: Cristina
authors.initials: C
authors.lastname: Álvarez
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.forename: Agustín
authors.initials: A
authors.lastname: Seoane
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Dedeu
authors.forename: Anna
authors.initials: A
authors.lastname: Abulí
authors.forename: Lucas
authors.initials: L
authors.lastname: Ilzarbe
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.forename: Maria
authors.initials: M
authors.lastname: Pellise
authors.forename: Francesc
authors.initials: F
authors.lastname: Balaguer
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellvi-Bel
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics; D002288:Adenocarcinoma, Mucinous / Q000453:epidemiology / Q000235:genetics; D000368:Aged; D018276:Carcinoma, Medullary / Q000453:epidemiology / Q000235:genetics; D018279:Carcinoma, Signet Ring Cell / Q000453:epidemiology / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012680:Sensitivity and Specificity; D013030:Spain / Q000453:epidemiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein