Gene expression signature for predicting homologous recombination deficiency in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers and may also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a gene expression-based machine learning classifier for homologous recombination deficiency (HRD) in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.93 in MyBrCa validation datasets and 0.84 in TCGA TNBCs. Additionally, the classifier strongly segregated HRD-associated genomic features in TNBCs from TCGA, METABRIC, and ICGC. Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy.

Germline APOBEC3B deletion increases somatic hypermutation in Asian breast cancer that is associated with Her2 subtype, PIK3CA mutations and immune activation.

A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is >5 times more common in women of Asian descent compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3'UTR, and it 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 nonhypermutated 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.

The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences.

Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

Oncogenic effects of WNT5A in Epstein-Barr virus­associated nasopharyngeal carcinoma.

The molecular events that drive the progression of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) are still to be elucidated. Here, we report for the first time the pathogenic significance of an NPC-associated gene, wingless-type MMTV integration site family, member 5A (WNT5A) and the contribution of EBV to its expression. WNT5A is a representative Wnt protein that activates non-canonical Wnt signalling. With regard to its role in carcinogenesis, there is conflicting evidence as to whether WNT5A has a tumour-promoting or tumour-suppressive role. We show that WNT5A is upregulated in primary NPC tissue samples. We also demonstrate that WNT5A expression was dramatically increased in NPC cell lines expressing the EBV-encoded LMP2A gene, suggesting that this EBV-encoded latent gene is responsible for upregulating WNT5A in NPC. In addition, in vitro WNT5A overexpression promotes the proliferation, migration and invasion of NPC cells. Our results not only reveal pro-tumorigenic effects of WNT5A in NPC but also suggest that WNT5A could be an important therapeutic target in patients with EBV-associated disease.