Novel Genetic Markers for Early Detection of Elevated Breast Cancer Risk in Women

• Main Authors: Bohua Wu, Yunhui Peng, Julia Eggert, Emil Alexov
• Format: Article
• Language: English
• Published: MDPI AG 2019-09-01
• Series: International Journal of Molecular Sciences
• Subjects: msh2; breast cancer; personalized medicine; early diagnostics; computational modeling; disease-causing mutations; variants
• Online Access: https://www.mdpi.com/1422-0067/20/19/4828

This study suggests that two newly discovered variants in the <i>MSH2</i> gene, which codes for a DNA mismatch repair (MMR) protein, can be associated with a high risk of breast cancer. While variants in the MSH2 gene are known to be linked with an elevated cancer risk, the MSH2 gene is not a part of the standard kit for testing patients for elevated breast cancer risk. Here we used the results of genetic testing of women diagnosed with breast cancer, but who did not have variants in <i>BRCA1</i> and <i>BRCA2</i> genes. Instead, the test identified four variants with unknown significance (VUS) in the <i>MSH2</i> gene. Here, we carried in silico analysis to develop a classifier that can distinguish pathogenic from benign mutations in <i>MSH2</i> genes taken from ClinVar. The classifier was then used to classify VUS in <i>MSH2</i> genes, and two of them, p.Ala272Val and p.Met592Val, were predicted to be pathogenic mutations. These two mutations were found in women with breast cancer who did not have mutations in <i>BRCA1</i> and <i>BRCA2</i> genes, and thus they are suggested to be considered as new bio-markers for the early detection of elevated breast cancer risk. However, before this is done, an in vitro validation of mutation pathogenicity is needed and, moreover, the presence of these mutations should be demonstrated in a higher number of patients or in families with breast cancer history.