Spatial patterns of APOBEC mutagenesis in the tumour microenvironment of Asian breast cancer

Abstract

A germline deletion of the coding region at the APOBEC3B (A3B) gene that is common in Asian and Oceanic populations has been found to be correlated with increased APOBEC mutagenesis, immune activation, and tumour heterogeneity in breast cancer. The mechanism by which A3B deletion and APOBEC mutagenesis induces immune activation in Asian breast cancers is still unclear, but has been thought to involve increased neoantigen burden. In this study, we investigated the mechanisms by which A3B deletion and APOBEC mutagenesis may lead to immune activation using Stereo-seq spatial transcriptomics of Malaysian triple-negative breast cancer (TNBC) tumours with and without the A3B deletion to examine the spatial expression patterns of APOBEC3A/B as well the spatial patterns of APOBEC-associated mutations and neoantigens. Unexpectedly, we found only limited associations between A3B deletion, APOBEC-associated neoantigens, and immune activation. Instead, we found strong spatial associations between mitochondrial APOBEC-associations mutations, the cGAS-STING pathway, and the NF-{kappa}B pathway. Our study thus supports a new model whereby APOBEC-mediated activation of the immune system does not occur via neoantigen presentation, but instead occurs via mitochondrial hypermutation that drives cGAS-STING activation of the NF-{kappa}B pathway. Our study may provide new insights into the spatial landscape of Asian breast tumours and the effect of germline A3B deletion and APOBEC mutagenesis on the tumour immune microenvironment.