Cancers with Pathogenic BRCA1/2 Mutations

The BRCA1 and BRCA2 genes have a role in the accurate repair of DNA double-strand breaks through homologous recombination deficiency.¹ A mutational signature of BRCA1/2 loss consists of multiple mutation types (point mutations, indels, structural and copy number variants).² The exact mechanisms of how such mutations form in the context of homologous recombination deficiency have not been fully understood.

From the PCAWG study, we retrieved 44 whole genomes of cancer samples with bi-allelic loss of BRCA1 or BRCA2 genes, which were identified based on the published curations of germline mutations in the two genes.³

Through Chromoscope, we can visualize and compare characteristics between the genome of BRCA1 or BRCA2 cancers. The visualization shows that while both display general chromosomal instability, BRCA1 cancers show the predominance of tandem duplications, while deletions dominate BRCA2 cancers. Additionally, the telomeric loss-of-heterozygosity segments characteristic of homologous recombination deficiency, often appear to be delineated by unbalanced translocations (example).

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The cohort of 44 cancer genomes with BRCA1/2 loss is accessible through the following Chromoscope configuration:

https://chromoscope.bio/app/?showSamples=true&external=https://somatic-browser-test.s3.amazonaws.com/pathogenicBrca/configs/pathogenicBrca.all.config.json

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1. Helleday, T. et al. Mechanisms underlying mutational signatures in human cancers. Nature reviews. Genetics vol. 15,9 (2014): 585-98. doi:10.1038/nrg3729↩
2. Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nature medicine vol. 23,4 (2017): 517-525. ↩
3. Nguyen, L., et al. Pan-cancer landscape of homologous recombination deficiency. Nature Communications, 11(1), 5584 (2020).↩