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

BMC Cancer

Research Article

Mev Dominguez Valentin¹  Ligia Petrolini de Oliveira¹  Benedito Mauro Rossi¹  Fabio de Oliveira Ferreira²  Samuel Aguiar Junior²  Felipe Carneiro³  Erika Maria Monteiro Santos³  Dirce Maria Carraro³  Israel Gomy⁴  Wilson Toshihiko Nakagawa⁵  Victor Evangelista de Faria Ferraz⁶  Wilson Araujo da Silva Junior⁶ 

[1] Graduation Program, AC Camargo Hospital, Sao Paulo, Brazil;Graduation Program, AC Camargo Hospital, Sao Paulo, Brazil;Hereditary Colorectal Cancer Registry, AC Camargo Hospital, Sao Paulo, Brazil;Graduation Program, AC Camargo Hospital, Sao Paulo, Brazil;International Center of Research and Training (CIPE), AC Camargo Hospital, Sao Paulo, Brazil;Graduation Program, AC Camargo Hospital, Sao Paulo, Brazil;Sao Paulo University, Department of Genetics, Medical School of Ribeirao Preto, Ribeirao Preto, Brazil;Hereditary Colorectal Cancer Registry, AC Camargo Hospital, Sao Paulo, Brazil;Sao Paulo University, Department of Genetics, Medical School of Ribeirao Preto, Ribeirao Preto, Brazil;

关键词: Genetic Counselling;    Endometrial Cancer;    Lynch Syndrome;    Risk Prediction Model;    Amsterdam Criterion;   

DOI  :  10.1186/1471-2407-12-64

 received in 2011-07-30, accepted in 2012-02-09,  发布年份 2012

来源: Springer

【 摘 要 】

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

【 授权许可】

Unknown   
© Santos et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.