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.
Balaguer
Francesc
F
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.
Balmaña
Judith
J
Castellví-Bel
Sergi
S
Steyerberg
Ewout W
EW
Andreu
Montserrat
M
Llor
Xavier
X
Jover
Rodrigo
R
Syngal
Sapna
S
Castells
Antoni
A
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