Landscape analysis of adjacent gene rearrangements reveals BCL2L14–ETV6 gene fusions in more aggressive triple-negative breast cancer

Triple-negative breast cancer (TNBC) accounts for 10 to 20% of breast cancer, with chemotherapy as its mainstay of treatment due to lack of well-defined targets, and recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations. Recurrent gene fusions comprise a class of viable genetic targets in solid tumors; however, their role in breast cancer remains underappreciated due to the complexity of genomic rearrangements in this cancer. Our interrogation of the whole-genome sequencing data for 215 breast tumors catalogued 99 recurrent gene fusions, 57% of which are cryptic adjacent gene rearrangements (AGRs). The most frequent AGRs, BCL2L14–ETV6, TTC6–MIPOL1, ESR1–CCDC170, and AKAP8–BRD4, were preferentially found in the more aggressive forms of breast cancers that lack well-defined genetic targets. Among these, BCL2L14–ETV6 was exclusively detected in TNBC, and interrogation of four independent patient cohorts detected BCL2L14–ETV6 in 4.4 to 12.2% of TNBC tumors. Interestingly, these fusion-positive tumors exhibit more aggressive histopathological features, such as gross necrosis and high tumor grade. Amid TNBC subtypes, BCL2L14–ETV6 is most frequently detected in the mesenchymal entity, accounting for ∼19% of these tumors. Ectopic expression of BCL2L14–ETV6 fusions induce distinct expression changes from wild-type ETV6 and enhance cell motility and invasiveness of TNBC and benign breast epithelial cells. Furthermore, BCL2L14–ETV6 fusions prime partial epithelial–mesenchymal transition and endow resistance to paclitaxel treatment. Together, these data reveal AGRs as a class of underexplored genetic aberrations that could be pathological in breast cancer, and identify BCL2L14–ETV6 as a recurrent gene fusion in more aggressive form of TNBC tumors.