APOBEC3 Hypermutation Detection in Metastatic Breast Cancer via Targeted Next-Generation Sequencing

APOBEC3 proteins contribute to immune defense via cytosine deamination, but off-target activity on chromosomal DNA can increase mutational burden, tumor heterogeneity, and therapy resistance in breast cancer. APOBEC3 activity has primarily been characterized using comprehensive sequencing rather than targeted panels used in clinical practice. Here, we present a case of metastatic breast cancer with APOBEC3-mediated hypermutation identified by mutational signature analysis using a targeted next-generation sequencing (NGS) panel. A 70-year-old woman treated for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer developed bone metastases nearly 20 years later. Targeted NGS revealed a high tumor mutational burden (37.08 mutations/Mb). Mutational signature analysis identified COSMIC single-base substitution signatures 2 and 13, which are characteristic of APOBEC3 activity and together accounted for 87.3% of the mutations. Targeted NGS-based mutational signature analysis may identify APOBEC3-mediated hypermutation in selected hypermutated tumors as a complementary, exploratory approach.