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Triple-negative breast cancers (TNBCs) are a subset of breast cancers that has remained difficult to treat. One of the more efficient treatments for TNBCs is by targeting the homologous recombination (HR) pathway, for example using PARP inhibitors, that has benefited TNBC patients carrying BRCA1/2 alterations. We developed a method to identify TNBC patients, regardless of their BRCA1/2 status, who may benefit from therapies targeting the HR pathway. Using an RNA-seq gene expression dataset of 100 genes (HRD100) from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a nearest centroid classifier for homologous recombination deficiency (HRD) in TNBCs. The HRD100 classifier identified samples with strong HRD mutational signature at an AUROC of 0.892 in the MyBrCa training dataset, as well as 0.783 and 0.713 in MyBrCa and TCGA validation datasets, respectively. Analysis of the 100 genes in the HRD100 classifier using the NanoString nCounter platform showed a concordance rate of 98% (CI: 95-100%) with RNA-seq gene expression analyses, and a concordance rate of 87% (CI: 73-100%) between FFPE and fresh frozen tissue. Taken together, gene expression using these 100 selected genes may identify triple-negative breast cancer patients with homologous recombination deficiency who may benefit from treatment with PARP inhibitors or platinum chemotherapy.

A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3'UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between the A3B deletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germline A3B deletion polymorphism leads to expression of the A3A-B hybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless of A3B germline status, were associated with the Her2 molecular subtype and PIK3CA mutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germline A3B deletion polymorphism, via the A3A-B hybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless of A3B background, may be an important clinical biomarker for Asian breast cancers. This article is protected by copyright. All rights reserved.