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BMC Cancer. 2012; 12: 64.
Published online Feb 9, 2012. doi:  10.1186/1471-2407-12-64
PMCID: PMC3305354
Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries
Erika Maria Monteiro Santos,corresponding author#1,2 Mev Dominguez Valentin,#1 Felipe Carneiro,#1,2 Ligia Petrolini de Oliveira,#1 Fabio de Oliveira Ferreira,#1,3 Samuel Aguiar Junior,#1,3 Wilson Toshihiko Nakagawa,#3 Israel Gomy,#1,4 Victor Evangelista de Faria Ferraz,#4 Wilson Araujo da Silva Junior,#4 Dirce Maria Carraro,#1,2 and Benedito Mauro Rossi#1
1Graduation Program, AC Camargo Hospital, Sao Paulo, Brazil
2International Center of Research and Training (CIPE), AC Camargo Hospital, Sao Paulo, Brazil
3Hereditary Colorectal Cancer Registry, AC Camargo Hospital, Sao Paulo, Brazil
4Sao Paulo University, Department of Genetics, Medical School of Ribeirao Preto, Ribeirao Preto, Brazil
corresponding authorCorresponding author.
#Contributed equally.
Erika Maria Monteiro Santos: erikammsantos/at/gmail.com; Mev Dominguez Valentin: mv_dv/at/yahoo.com; Felipe Carneiro: carneirofelipe/at/hotmail.com; Ligia Petrolini de Oliveira: ligia.petrolini/at/gmail.com; Fabio de Oliveira Ferreira: fabioferreira/at/uol.com.br; Samuel Aguiar Junior: samuel.aguiar.jr/at/gmail.com; Wilson Toshihiko Nakagawa: wtnakagawa/at/uol.com.br; Israel Gomy: isgomy/at/gmail.com; Victor Evangelista de Faria Ferraz: vferraz/at/rge.fmrp.usp.br; Wilson Araujo da Silva Junior: wilsonjr/at/usp.br; Dirce Maria Carraro: dirce.carraro/at/cipe.accamargo.org.br; Benedito Mauro Rossi: rossibm/at/gmail.com
Received July 30, 2011; Accepted February 9, 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.
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