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Abstract
Introduction. More than 10% of breast cancer (BC) cases are hereditary or familial. The standard genetic analysis for hereditary BC focuses on the well-characterized BRCA1 and BRCA2 genes. However, a significant proportion of cases are associated with mutations in other genes. Furthermore, routine clinical molecular diagnostics is typically limited to the analysis of micromutations, and does not identify large genomic copy number variations (CNVs), which account for up to 10% of pathogenic alterations in BRCA1/2 and associated partner genes.
Aim. To analyze the frequency and spectrum of pathogenic germline variants, including large genomic rearrangements, in BC patients using an expanded gene panel.
Materials and Methods. Targeted next-generation sequencing of the coding regions of the ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FANCD2, NBN, PALB2, RAD51A, RAD51B, RAD51C, RAD51D, RAD54L, and TP53 genes was performed on 7,840 BC patients. Bioinformatic analysis included detection of single-nucleotide variants, micro insertions/deletions, and exon-level copy number analysis. Identified CNVs were verified using digital droplet PCR.
Results. A hereditary genetic cause was identified in 16.4 % (n=1,291) of patients. A combination of two pathogenic variants was detected in 43 cases. The frequency of pathogenic variants correlated with a positive family history and the presence of multiple primary cancers. Correlation with young age at diagnosis was observed only for BRCA1/2 mutations. Alterations in BRCA1 (26.9 %), BRCA2 (26 %), and CHEK2 (13.5 %) were predominated. Over a quarter of the detected point mutations were unique, while 41.0 % were recurrent variants. Large genomic rearrangements accounted for 9.2 % of all identified mutations. CNVs were most frequently found in the CHEK2 (35.4% of all pathogenic CHEK2 variants) and BRCA1 (7.1% of all pathogenic BRCA1 variants) genes. CNVs were also detected in ATM, BLM, BRCA2, PALB2, and RAD51C.
Conclusion. Expanding the gene panel and implementing routine CNV analysis alongside point mutation detection can allow for better BC patient stratification and optimization of therapeutic strategies.
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