Gastroenterology

Gastroenterology

Volume 140, Issue 1, January 2011, Pages 73-81.e5
Gastroenterology

Clinical—Alimentary Tract
The PREMM1,2,6 Model Predicts Risk of MLH1, MSH2, and MSH6 Germline Mutations Based on Cancer History

https://doi.org/10.1053/j.gastro.2010.08.021Get rights and content

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; 1.5–2.4), 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 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.

Section snippets

Patients

We analyzed a previously unreported study cohort of 4893 consecutive probands unknown to be related who submitted blood samples for full gene sequencing of MLH1, MSH2, and MSH6 to Myriad Genetic Laboratories, Inc (Salt Lake City, UT) after 2005. Testing was ordered by health care professionals for individuals with a personal or family history suggestive of Lynch syndrome. Data were obtained from the test order form completed by health care professionals ordering clinical genetic testing. Data

Univariate Analysis

Pathogenic mutations were found in 525 of 4539 subjects (12%), with 204 MLH1, 250 MSH2, and 71 MSH6 gene mutations detected. A majority of individuals undergoing genetic testing were women (73%; Table 1). However, the frequency of mutations detected was highest among men; 190 of 1214 men (16%) carried a gene mutation compared with 335 of 3325 women (10%). Six percent of mutation carriers (31/525) were unaffected by CRC or other Lynch syndrome–associated cancers compared with 896 of 4014

Discussion

We have developed and validated a clinical model to predict MMR gene mutations in the MLH1, MSH2, and MSH6 genes: the PREMM1,2,6 model. This model can estimate the probability of carrying an MMR gene mutation, as well as provide such risk estimates for each particular MMR gene based on an individual patient's personal and family cancer history phenotype, and performs equally well among patients with CRC recruited through population-based cancer registries.

The PREMM1,2,6 model is derived from

Acknowledgments

The authors acknowledge the following Colon Cancer Family Registries that provided data for the analysis: Australasian Colorectal Cancer Family Registry (U01 CA097735), University of Southern California Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794), and University

References (29)

  • K.M. Schmeler et al.

    Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome

    N Engl J Med

    (2006)
  • H.F.A. Vasen et al.

    The international collaborative group on HNPCC

    Dis Colon Rectum

    (1991)
  • M.A. Rodriquez-Bigas et al.

    An NCI workshop on HNPCC: meeting highlights and Bethesda guidelines

    J Natl Cancer Inst

    (1997)
  • A. Umar et al.

    Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability

    J Natl Cancer Inst

    (2004)
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      Because health care providers may not effectively select individuals with personal and/or family history of CRC for genetic evaluation or for evaluation of Lynch syndrome,50 computer-based prediction models have been developed to systematically assess risk of Lynch syndrome. These risk models include the prediction of MMR gene mutations (PREMM),51–53 MMRPredict,54 and MMRpro.55 The PREMM model has been most extensively validated, has been updated to include all the Lynch syndrome–related genes, and is used in clinical practice.56–58

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    Conflicts of interest The authors disclose the following: Ms Burbidge and Dr Wenstrup report employment and stock or other ownership interests in Myriad Genetics Laboratories, Inc. The remaining authors disclose no conflicts relevant to the data presented in the article.

    Funding Supported by the National Cancer Institute (grants R01CA132829 [to S.S.] and K24 CA113433 [to S.S.]). Recruitment, data collection, and genetic testing for the Colon Cancer Family Registry work were supported by the National Cancer Institute, National Institutes of Health (CA-95011), and through cooperative agreements with the members of the Colon Cancer Family Registry and principal investigators.

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