Breast cancer (BC) represents the most common malignancy and has the highest mortality among women, both in the world and in Kazakhstan. Approximately 20-30% of cases of hereditary breast cancer are caused by presence of BRCA1 and BRCA2 genes defects. Also, there are additional genes which can increase the risk of BC and they are still under study.The aim of this study was to identify new, detectable and objective markers of key cancer genes by next-generation sequencing (NGS) in BC patients.
The study included 194 unrelated patients (the av/age 34.25 ± 4.56) with BC. Genomic DNA was obtained from peripheral blood,next-generation sequencing was performed using TruSightCancer Kit on the MiSeq platform,studio Variant was used to annotate genetic variants.
In total, 61 pathogenic variants (all in heterozygous state) were found in 56 (28.9%) patients,the vast majority of variants located in BRCA1 (n = 19/56; 33.9%), 15 in BRCA2 (26.8%). The frequency of pathogenic variants in genes TP53 (8.9%), PALB2 (5.4%), MSH6 (5.4%), CHEK2 (3.6%), SDHB (3.6%), and WRN (3.6%) were higher than those genes APC, ATM, FANCA, FANCM, MSH2, NBN, NF1, PMS1, PMS2, and XPA which include only one deleterious variants. The analysis of mutation type has revealed 28 frameshift mutations, 15 stop-gain mutations, 8 missense mutations, 8 splice site variants, 1 start lost variant, and 1 synonymous variant. In total, 43 mutations were unique, 15 of them represented novel variants. Those new mutations have not been previously mentioned in the LOVD and ClinVar databases and have not been described in publications. Population frequency of all detected pathogenic mutations in 1000G, ESP6500 and ExAC databases were less than 1%. 73.8% of the mutations were available in the dbSNP database. The most common pathogenic variants were c.5329dupC and c.5341-2delA (c.5278-2delA) in BRCA1 gene, accounting for 10.7% (n = 6/56) and 8.9% of patients (n = 5/56), respectively.
NGS showed frequent and novel germline mutations in BRCA1/2, CHEK2, TP53 and PALB2. After the final statistical data processing, diagnostic and prevention tools for key genes will be developed and included in the National guidelines for cancer diseases.
Kazakh Institute of Oncology and Radiology Institute of General Genetics and Cytology.
The Ministry of Healthcare of the Republic of Kazakhstan.
All authors have declared no conflicts of interest.