Validation and extension of the PREMM1,2 model in a population-based cohort of colorectal cancer patients.
OBJECTIVE
Early recognition of patients at risk for Lynch syndrome is critical but often difficult. Recently, a predictive algorithm-the PREMM(1,2) model-has been developed to quantify the risk of carrying a germline mutation in the mismatch repair (MMR) genes MLH1 and MSH2. However, the model's performance in an unselected, population-based colorectal cancer population as well as its performance in combination with tumor MMR testing are unknown.


METHODS
We included all colorectal cancer cases from the EPICOLON study, a prospective, multicenter, population-based cohort (n = 1222). All patients underwent tumor microsatellite instability analysis and immunostaining for MLH1 and MSH2, and those with MMR deficiency (n = 91) underwent tumor BRAF V600E mutation analysis and MLH1/MSH2 germline testing.


RESULTS
The PREMM(1,2) model with a >/=5% cut-off had a sensitivity, specificity, and positive predictive value (PPV) of 100%, 68%, and 2%, respectively. The use of a higher PREMM(1,2) cut-off provided a higher specificity and PPV, at expense of a lower sensitivity. The combination of a >/=5% cut-off with tumor MMR testing maintained 100% sensitivity with an increased specificity (97%) and PPV (21%). The PPV of a PREMM(1,2) score >/=20% alone (16%) approached the PPV obtained with PREMM(1,2) score >/=5% combined with tumor MMR testing. In addition, a PREMM(1,2) score of <5% was associated with a high likelihood of a BRAF V600E mutation.


CONCLUSIONS
The PREMM(1,2) model is useful to identify MLH1/MSH2 mutation carriers among unselected colorectal cancer patients. Quantitative assessment of the genetic risk might be useful to decide on subsequent tumor MMR and germline testing.
Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Catalonia, Spain.
Francesc
F
Balaguer
Judith
J
Balmaña
Sergi
S
Castellví-Bel
Ewout W
EW
Steyerberg
Montserrat
M
Andreu
Xavier
X
Llor
Rodrigo
R
Jover
Sapna
S
Syngal
Antoni
A
Castells
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D006580:Genetic Carrier Screening / Q000379:methods*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013030:Spain / Q000453:epidemiology
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins