Analysis of non-BRCA1/2 predisposition genes by next generation sequencing in familial breast cancer cases

Objective: Breast cancer is one of the most common cancers among women. In the familial cases, the most prominent pathogenic mutations belong to BRCA1 and BRCA2 genes. However, pathogenic mutations cannot be detected in some patients, in spite of the presence of strong family history. In this study, we have aimed to detect pathogenic mutations in non-BRCA1/2 genes which thought to be involved in familial cancer syndromes. Method: Fifteen eligible patients having a strong family history and not carrying any pathogenic mutation in BRCA1/2 genes were involved in this study. All the coding regions of 14 genes (ATM, BARD1, BRIP1, CDH1, CHEK2, MRE11A, MSH6, NBN, PALB2, PTEN, RAD51, RAD51C, STK11, TP53) related to familial cancer syndromes were sequenced by next-generation sequencing and detected pathogenic mutations were confirmed via Sanger method. The results were evaluated by comparing with current literature and databases. Results: As a result of multiple gene panel sequencing, pathogenic mutations were detected in CHEK2 and MSH6 genes in about 26% of cases. In this study, c.1312G> T and c.470T>C missense mutations, and c.715G> T nonsense mutation in CHEK2 gene, also c.1628A> C missense mutation in MSH6 gene were detected in different patients. To our knowledge, the mutation in MSH6 gene was detected for the first time in this study. In addition, certain variant of uncertain significance and low-risk variant for breast cancer were detected. Conclusion: Familial breast cancer is a heterogeneous disease. It can occur in several mechanisms depending on the genetic background of the cases and the effect of the environment. Our findings might have a significant impact on understanding of genetic etiology of familial breast cancer, genetic counseling and diagnosis. To understand disease mechanism further studies large population-based and functional studies are required.