Evaluation of germ line mutational status among women with triple-negative breast cancer in Russia

Abstract

Abstract Background Pathogenic germline BRCA1/2 mutations are found in higher rates in patients with triple negative breast cancer (TNBC). As a result, genetic BRCA mutation testing would be beneficial for this particular group of patients. At the same time, it is less clear if mutational burden in other cancer predisposition genes is more frequent in TNBC and has to be recommended for genetic testing. In the current study we aimed to characterize pathogenic germline mutations in TNBC patients fulfilling NCCN criteria of hereditary cancers from Russian Federation. Methods Individuals with diagnosis of TNBC were selected to be included in this study according based on the following criteria: (1) young age of disease onset, (2) the presence of relatives with breast or ovarian cancer diagnosis. The NimbleGen SeqCap EZ Choice kit (“Roche”) was used for target enrichment, and sequencing was performed using Illumina MiSeq (“Illumina”). Custom bioinformatic pipeline, including Annovar, HGMD Professional 2017.4 and BIC databases were used to identify pathogenic mutations. Results 128 patients with triple negative breast cancer aged from 24 to 79 years old were included in this study. 42 woman has their first cancer diagnosis before 40 years old, 77 – between 41 and 60 years old, 9 - were older than 60. 42 patients (33%) carried pathogenic or likely pathogenic variant in BRCA1 gene,10 (8%) in BRCA2 gene and 40 (31%) in one of other genes, including BUB1, CDH1, CDKN2A, CHEK2, EPCAM, FANCI, MLH3, MSH6, PALB2, PMS2, POLE, POLE, RAD50, RBBP8, RET, STK11, APC, ATM, BARD1, BLM. 13 woman had double mutation in two genes, and one patient had double mutation in BRCA1 gene. For the BRCA1 carriers subgroup, the median age at diagnosis was 41(24-64), BRCA2 carriers – 44 (27-62) and other genes carriers – 48 (28-79) year old. Patients with double mutation had median age of cancer manifestation at 42 (32-65). Conclusions Approximately 38% of patients with TNBC fulfilling NCCN criteria of hereditary cancer are carriers of pathogenic and likely pathogenic mutations in BRCA1 and BRCA2 genes. And up to 40% - in other cancer susceptibility genes. Thus, the patients with TNBC might be recommended for extended genetic testing depending on age of onset and the presence of a cancer family history. Legal entity responsible for the study Tatarstan Cancer Center. Funding The work is supported by Russian Foundation for Basic Research № 18-415-160009 and according to the Russian Government Program of Competitive Growth of Kazan Federal University. Disclosure All authors have declared no conflicts of interest.