title: Performance of Lynch syndrome predictive models in a multi-center US referral population.
abstract: OBJECTIVE
  Lynch syndrome is the most common cause of inherited colorectal cancer (CRC) and is due to germline mutations in mismatch repair (MMR) genes. Early Lynch syndrome diagnosis and appropriate CRC surveillance improves mortality. Traditional qualitative clinical criteria including Amsterdam and Bethesda guidelines may miss mutation carriers. Recently, quantitative predictive models including MMRPredict, PREMM(1,2,6), and MMRPro were developed to facilitate diagnosis. However, these models remain to be externally validated in the United States. Therefore, we evaluated the test characteristics of Lynch syndrome predictive models in a tertiary referral group at two US academic centers.
  
  
  METHODS
  We retrospectively collected data on 230 consecutive individuals who underwent genetic testing for MMR gene mutations at the University of Chicago and University of California at San Francisco's Cancer Risk Clinics. Each individual's risk of mutation was examined using MMRPredict, PREMM(1,2,6), and MMRPro. Amsterdam and Bethesda criteria were also determined. Testing characteristics were calculated for each of the models.
  
  
  RESULTS
  We included 230 individuals in the combined cohort. In all, 113 (49%) probands were MMR mutation carriers. Areas under the receiver operator characteristic curves were 0.76, 0.78, and 0.82 for MMRPredict, PREMM(1,2,6), and MMRPro, respectively. While similar in overall performance, our study highlights unique test characteristics of these three quantitative models including comparisons of sensitivity and specificity. Moreover, we identify characteristics of mutation carriers who were missed by each model.
  
  
  CONCLUSIONS
  Overall, all three Lynch syndrome predictive models performed comparably in our multi-center US referral population. These results suggest that Lynch syndrome predictive models can be used to screen for MMR mutation carriers and can provide improved test characteristics compared with traditional clinical criteria. Identification of MMR mutation carriers is paramount as appropriate screening can prevent CRC mortality in this high-risk group.
authors: Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Illinois 60637, USA.
authors: Omar
authors: O
authors: Khan
authors: Amie
authors: A
authors: Blanco
authors: Peggy
authors: P
authors: Conrad
authors: Cassandra
authors: C
authors: Gulden
authors: Tovah Z
authors: TZ
authors: Moss
authors: Olufunmilayo I
authors: OI
authors: Olopade
authors: Sonia S
authors: SS
authors: Kupfer
authors: Jonathan
authors: J
authors: Terdiman
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012372:ROC Curve; D012107:Research Design; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D014481:United States / Q000453:epidemiology