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Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Comparison of predictive models, clinical criteria and molecular tumour screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients

Department of Medical Oncology, Hospital Vall d'Hebron, Medical Department of Universitat Autónoma de Barcelona, Spain.
Journal of Medical Genetics (Impact Factor: 5.64). 07/2008; 45(9):557-63. DOI: 10.1136/jmg.2008.059311
Source: PubMed

ABSTRACT Several models have recently been developed to predict mismatch repair (MMR) gene mutations. Their comparative performance with clinical criteria or universal molecular screening in a population based colorectal cancer (CRC) cohort has not been assessed.
All 1222 CRC from the EPICOLON cohort underwent tumour MMR testing with immunohistochemistry and microsatellite instability, and those with MMR deficiency (n = 91) underwent MLH1/MSH2 germline testing. Sensitivity, specificity and positive predictive value (PPV) of the PREMM(1,2) and the Barnetson models for identification of MLH1/MSH2 mutation carriers were evaluated and compared with the revised Bethesda guidelines (RBG), Amsterdam II criteria, and tumour analysis for MMR deficiency. Overall discriminative ability was quantified by the area under the ROC curve (AUC), and calibration was assessed by comparing the average predictions versus the observed prevalence.
Both models had similar AUC (0.93 and 0.92, respectively). Sensitivity of the RBG and a PREMM(1,2) score > or =5% was 100% (95% CI 71% to 100%); a Barnetson score >0.5% missed one mutation carrier (sensitivity 87%, 95% CI 51% to 99%). PPVs of all three strategies were 2-3%. Presence of MMR deficiency increased specificity and PPV of predictive scores (97% and 21% for PREMM(1,2) score > or =5%, and 98% and 21% for Barnetson > or =0.5%, respectively).
The PREMM(1,2) and the Barnetson models offer a quantitative systematic approach to select CRC patients for identification of MLH1/MSH2 mutation carriers with a similar performance to the RBG.

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    • "Up until now, models predicting the risk of germline mutations in patients with CRC were evaluated in consecutive samples [20-27] and in patients at high risk due to the positive family history [28-30]. In these studies, samples from Latin American populations were always underrepresented. "
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    ABSTRACT: Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson). The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.
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    ABSTRACT: Lynch syndrome is the most common hereditary colorectal cancer syndrome, responsible for 3-5% of all colorectal cancer (CRC) cases. In addition, tumors of the endometrium, ovaries, stomach, small bowel, biliary tract, urinary tract, skin and brain occur at higher frequencies compared to the general population. Mutations in at least four different mismatch repair (MMR) genes, including MLH1, MSH2, MSH6 and PMS2, are the underlying defect in Lynch syndrome. The introduction in chapter 2 gives a general overview of different aspects of Lynch syndrome. Clinical features, cancer risks, diagnostic strategies, surveillance and management of Lynch syndrome are discussed. The identification of Lynch syndrome is still suboptimal, mainly due to the lack of specific diagnostic features. Early identification of Lynch syndrome is important for optimal surveillance.
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