Title
Predictive models for mutations in mismatch repair genes: Implication for genetic counseling in developing countries
Date Issued
09 February 2012
Access level
open access
Resource Type
journal article
Author(s)
Monteiro Santos E.M.
Carneiro F.
de Oliveira L.P.
de Oliveira Ferreira F.
Junior S.A.
Nakagawa W.T.
Gomy I.
de Faria Ferraz V.E.
da Silva Junior W.A.
Carraro D.M.
Rossi B.M.
AC Camargo Hospital
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. © 2012 Santos et al; licensee BioMed Central Ltd.
Volume
12
Language
English
OCDE Knowledge area
Genética humana
Scopus EID
2-s2.0-84858148591
PubMed ID
Source
BMC Cancer
Source funding
Fundação de Amparo à Pesquisa do Estado de São Paulo
Sponsor(s)
This study was funding by FAPESP (Sao Paulo State Research Support Foundation-funding number 05/05155-6) and CNPq (National Council of Scientific and Technologic Development-number 408833/2006-8).
Sources of information:
Directorio de Producción Científica
Scopus