Validation of the PREMM1,2 model for the prediction of MLH1/MSH2 germline mutation carriers in a population- based cohort of colorectal cancer (CRC) patients

10545 Background: PREMM1,2 is a predictive model for estimating the likelihood of finding a mutation in the MLH1 and MSH2 genes developed in a population at risk of Lynch syndrome (Balmaña et al. JAMA 2006). The EPICOLON cohort is a Spanish population-based series of 1222 patients with CRC (Piñol et al. JAMA 2005). Methods: All 1222 individuals underwent microsatellite instability (MSI) and immunohistochemistry (IHC) analysis for MLH1/MSH2. Patients whose tumours exhibited MSI or altered IHC underwent MLH1/MSH2 analysis (n=91). Sensitivity (Se), specificity, positive predictive value (PPV), and the areas under the receiver operating characteristics curves (AUC) for the PREMM1,2 model were calculated and compared with the Edinburgh model (Barnetson et al. NEJM 2006) and the Revised Bethesda guidelines (RBG). Results: Three-hundred and ninety six individuals (32%) had a PREMM1,2 score =5%, 287 (23%) fulfilled the RBG, and 75 (6%) had a Barnetson score =5%. A PREMM1,2 score =5% and the RBG identified all carriers with deleterious mutations (n=8, Se=100%), while a Barnetson score =5% missed 2 mutation carriers (Se= 75%). For PREMM1,2 and Barnetson scores =5% and fulfilment of the RBG, specificities were 68%, 94%, and 77%, respectively; and PPV were 2%, 8%, and 2.8%, respectively. The AUC was 0.93 (95% CI: 0.86–0.99) for the PREMM1,2 model and 0.86 (95% CI: 0.66–1.04) for the Barnetson model. The predictions of carrying a mutation stratified into five groups based on PREMM1,2 scores (<5%, 5–9%, 10–19%, 20–39%, =40%) correlated reasonably with the presence of mutations (0%, 1%, 1%, 13%, and 22%, respectively). Conclusions: In a population of CRC patients, the PREMM1,2 model identifies all mutation carriers of MSH2 and MLH1 using a cutoff of =5%. In addition, it provides quantification of risk that is useful to decide the strategy used for molecular evaluation and risk counselling of patients. No significant financial relationships to disclose.

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TUMOUR PATHOLOGY PREDICTS MICROSATELLITE INSTABILITY IN A POPULATION-BASED SERIES OF COLORECTAL CANCER CASES

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4807 ◽

2008 ◽

Vol 31 (4) ◽

pp. 12

Author(s):

A J Hyde ◽

D Fontaine ◽

R C Green ◽

M Simms ◽

P S Parfrey ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Population Based ◽

Pathological Features ◽

Predictive Tool ◽

Entire Cohort ◽

Dna Mismatch ◽

Bethesda Guidelines ◽

Revised Bethesda Guidelines

Background: Lynch Syndrome is an autosomal dominant trait that accounts forapproximately 3% of all cases of colorectal cancer (CRC). It is caused by mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 or MSH2. These MMR defects cause high levels of microsatellite instability (MSI-H) in the tumours. MSI testing of all CRCs to identify potential Lynch Syndrome cases is not practical, so the Bethesda Guidelines, which use clinical and pathological features, were created to identify those tumours most likely to be MSI-H^1. In 2007 Jenkins et. al. created MsPath, a tool based on the pathological features described in the rarely used 3^rd Bethesda criterion, to improve prediction of MSI-H tumours among CRC cases diagnosed before age 60 years^2. Methods: We collected a population-based cohort of 716 CRC cases diagnosed before age 75 years in Newfoundland. For each of these cases we collected family history, performed MSI analysis, and scored a number of pathological features for the purpose of evaluating the accuracy of the Bethesda Criteria and MsPath at predicting MSI-H tumours. Results: Our work validates the MsPath tool in the Newfoundland population for the same age group used to create the tool. We found it identified MSI-H cases with a sensitivity of 95% and specificity of 35% in our population of CRCcases diagnosed before age 60 years (n=290). We also tested this tool on our older population of CRCcases, diagnosed at ages 60 to 74 years (n=426). We found it to be at least as predictive in this population,with a sensitivity of 95% and a specificity of 42%. We then used our entire cohort (N=716) to compare MsPath with the other Bethesda criteria.Bethesda criteria 1, 2, 4 and 5 together predicted MSI-H cases with a sensitivity of 67% and a specificity of 51%. MsPath was better at identifying these cases, with a sensitivity of 95% and a specificity of 39%. Conclusions: We conclude that MsPath can be extended to include patients diagnosed with CRC before age 75 years. As well, we have found that MsPath is a better predictive tool than the Revised Bethesda Guidelines for identifying MSI-H cases within a population-based setting of colorectal cancer. References: 1. Umar, A. et. al. J Natl Cancer Inst 2004;96:261-8 2.Jenkins, M.A. et. al. Gastroenterology 2007;133:48-56

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