Clinical—Alimentary TractThe PREMM1,2,6 Model Predicts Risk of MLH1, MSH2, and MSH6 Germline Mutations Based on Cancer History
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
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2020, GastroenterologyCitation Excerpt :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
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.