TY - JOUR
T1 - The PREMM1,2,6 model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history
AU - Kastrinos, Fay
AU - Steyerberg, Ewout W.
AU - Mercado, Rowena
AU - Balmaña, Judith
AU - Holter, Spring
AU - Gallinger, Steven
AU - Siegmund, Kimberly D.
AU - Church, James M.
AU - Jenkins, Mark A.
AU - Lindor, Noralane M.
AU - Thibodeau, Stephen N.
AU - Burbidge, Lynn Anne
AU - Wenstrup, Richard J.
AU - Syngal, Sapna
N1 - Funding Information:
This work was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 , and through cooperative agreements with members of the Colon Cancer Family Registry and private investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government or the CFR.
PY - 2011/1
Y1 - 2011/1
N2 - Background & Aims: 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 (PREMM1,2,6) 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 PREMM1,2,6 model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.52.4), a CRC (4.3; 3.35.6), multiple CRCs (13.7; 8.522), endometrial cancer (6.1; 4.68.2), and extracolonic cancers (3.3; 2.44.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.820.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.830.92) for MSH2, and 0.81 (95% CI, 0.690.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.860.90) and the population-based cases (95% CI, 0.830.92). Conclusions:: We developed the PREMM1,2,6 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.
AB - Background & Aims: 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 (PREMM1,2,6) 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 PREMM1,2,6 model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.52.4), a CRC (4.3; 3.35.6), multiple CRCs (13.7; 8.522), endometrial cancer (6.1; 4.68.2), and extracolonic cancers (3.3; 2.44.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.820.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.830.92) for MSH2, and 0.81 (95% CI, 0.690.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.860.90) and the population-based cases (95% CI, 0.830.92). Conclusions:: We developed the PREMM1,2,6 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.
KW - Colon Cancer Family Registry
KW - Gene-Specific Risk Estimates
KW - Lynch Syndrome
KW - Prediction Model
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U2 - 10.1053/j.gastro.2010.08.021
DO - 10.1053/j.gastro.2010.08.021
M3 - Article
C2 - 20727894
AN - SCOPUS:78650513224
SN - 0016-5085
VL - 140
SP - 73-81.e5
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -