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Open Access Research article

Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries

Erika Maria Monteiro Santos12*, Mev Dominguez Valentin1, Felipe Carneiro12, Ligia Petrolini de Oliveira1, Fabio de Oliveira Ferreira13, Samuel Aguiar Junior13, Wilson Toshihiko Nakagawa3, Israel Gomy14, Victor Evangelista de Faria Ferraz4, Wilson Araujo da Silva Junior4, Dirce Maria Carraro12 and Benedito Mauro Rossi1

Author Affiliations

1 Graduation Program, AC Camargo Hospital, Sao Paulo, Brazil

2 International Center of Research and Training (CIPE), AC Camargo Hospital, Sao Paulo, Brazil

3 Hereditary Colorectal Cancer Registry, AC Camargo Hospital, Sao Paulo, Brazil

4 Sao Paulo University, Department of Genetics, Medical School of Ribeirao Preto, Ribeirao Preto, Brazil

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BMC Cancer 2012, 12:64  doi:10.1186/1471-2407-12-64

Published: 9 February 2012

Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.