title: Comparison of the clinical prediction model PREMM(1,2,6) and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer.
abstract: BACKGROUND
  Lynch syndrome is caused by germline mismatch repair (MMR) gene mutations. The PREMM(1,2,6) model predicts the likelihood of a MMR gene mutation based on personal and family cancer history.
  
  
  OBJECTIVE
  To compare strategies using PREMM(1,2,6) and tumour testing (microsatellite instability (MSI) and/or immunohistochemistry (IHC) staining) to identify mutation carriers.
  
  
  METHODS
  Data from population-based or clinic-based patients with colorectal cancers enrolled through the Colon Cancer Family Registry were analysed. Evaluation included MSI, IHC and germline mutation analysis for MLH1, MSH2, MSH6 and PMS2. Personal and family cancer histories were used to calculate PREMM(1,2,6) predictions. Discriminative ability to identify carriers from non-carriers using the area under the receiver operating characteristic curve (AUC) was assessed. Predictions were based on logistic regression models for (1) cancer assessment using PREMM(1,2,6), (2) MSI, (3) IHC for loss of any MMR protein expression, (4) MSI+IHC, (5) PREMM(1,2,6)+MSI, (6) PREMM(1,2,6)+IHC, (7) PREMM(1,2,6)+IHC+MSI.
  
  
  RESULTS
  Among 1651 subjects, 239 (14%) had mutations (90 MLH1, 125 MSH2, 24 MSH6). PREMM(1,2,6) discriminated well with AUC 0.90 (95% CI 0.88 to 0.92). MSI alone, IHC alone, or MSI+IHC each had lower AUCs: 0.77, 0.82 and 0.82, respectively. The added value of IHC+PREMM(1,2,6) was slightly greater than PREMM(1,2,6)+MSI (AUC 0.94 vs 0.93). Adding MSI to PREMM(1,2,6)+IHC did not improve discrimination.
  
  
  CONCLUSIONS
  PREMM(1,2,6) and IHC showed excellent performance in distinguishing mutation carriers from non-carriers and performed best when combined. MSI may have a greater role in distinguishing Lynch syndrome from other familial colorectal cancer subtypes among cases with high PREMM(1,2,6) scores where genetic evaluation does not disclose a MMR mutation.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. fk18@columbia.edu
authors.forename: Fay
authors.initials: F
authors.lastname: Kastrinos
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.forename: Rowena
authors.initials: R
authors.lastname: Mercado
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Robert
authors.initials: R
authors.lastname: Haile
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Loic
authors.initials: L
authors.lastname: LeMarchand
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D012372:ROC Curve; D012042:Registries; D055815:Young Adult