Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry

Abstract

Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case-control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74-30.16). We also identified a low-frequency deletion in NF1 associated with breast cancer risk (OR 1.93, 95% CI 1.14-3.42). In addition, we detected 56 deletions, including six putative protein-truncating deletions, in suspected breast predisposition genes. This is the first large study to systematically search for structural deletions in breast cancer predisposition genes. Many of the deletions, particularly those resulting in protein truncations, are likely to be pathogenic. Results from this study, if confirmed in future large-scale studies, could have significant implications for genetic testing for this common cancer.

Fig 1.. Eight protein-truncating SV deletions identified in established breast cancer predisposition genes.

SV deletions were detected in the coding regions of BRCA1, BRCA2, RAD51C, RAD51D, and TP53, and in the exonic regions of CDH1, CHEK2, and NF1. The coordinate of deletion is based on GRCh38 reference. The top line presents the gene structure with the exon marked by black boxes and strand direction marked by the black arrows. The dash line refers to the intergenic region affected by the SV deletion.