The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history.
OBJECTIVE
We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer.


METHODS
Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases.


RESULTS
Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92).


CONCLUSIONS
We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.
Kastrinos
Fay
F
Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York 10032, USA. fk18@columbia.edu
Steyerberg
Ewout W
EW
Mercado
Rowena
R
Balmaña
Judith
J
Holter
Spring
S
Gallinger
Steven
S
Siegmund
Kimberly D
KD
Church
James M
JM
Jenkins
Mark A
MA
Lindor
Noralane M
NM
Thibodeau
Stephen N
SN
Burbidge
Lynn Anne
LA
Wenstrup
Richard J
RJ
Syngal
Sapna
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D012306:Risk
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein