ABSTRACT
BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.
Subject(s)
Breast Neoplasms , Ovarian Neoplasms , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Female , Genes, BRCA2 , Genetic Predisposition to Disease , Germ Cells/pathology , Germ-Line Mutation , Humans , Male , Ovarian Neoplasms/genetics , TurkeyABSTRACT
Background: Mutations in the RAS genes, HRAS, KRAS, and NRAS, are the most common modifications in many types of human tumors and are found in approximately 30% of all human cancers. These mutations are usually found in codons 12, 13, or 61. Methods: The aim of this study is to evaluate mutations in codons 59, 117, and 146 of KRAS and NRAS genes in addition to codons 12,13, and 61 of KRAS gene in lung cancer tissue specimens obtained with bronchoscopy. KRAS and NRAS mutation analyses with pyrosequencing were performed on DNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue samples of 64 patients histopathologically diagnosed as lung cancer after bronchoscopic biopsy. Results: In all, 20 patients (31.2%) had mutations in KRAS gene (8/27 squamous cell carcinoma, 8/11 adenocarcinoma, 3/16 small cell carcinoma, and 1/1 pleomorphic carcinoma). The most common mutation in codon 12 was in c.35G>T (G12V). When the mutation rate of adenocarcinoma (72.7%) and squamous cell carcinoma (22.9%) patients was compared with each other, a statistically significant difference was observed (P = 0.008). There were no mutations in codons 59, 117, or 146 of KRAS and NRAS genes in patients with lung cancer. Conclusion: In this study, we firstly examined mutations in codons 59, 117, and 146 of KRAS and NRAS genes in addition to codons 12, 13, and 61 of KRAS gene in Turkish lung cancer patients both in non-small cell lung cancer and small cell lung cancer. Although no mutation was detected in codons 59, 117, and 146 of KRAS and NRAS genes, the frequency of KRAS gene mutation was higher than the rate of mutation in both Asian and Western countries, and multicenter studies including more cases should be performed to further explore our results.
