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

Abstract

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, <i>BCL2L14-ETV6</i>, <i>TTC6-MIPOL1</i>, <i>ESR1-CCDC170</i>, and <i>AKAP8-BRD4</i>, were preferentially found in the more aggressive forms of breast cancers that lack well-defined genetic targets. Among these, <i>BCL2L14-ETV6</i> was exclusively detected in TNBC, and interrogation of four independent patient cohorts detected <i>BCL2L14-ETV6</i> 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, <i>BCL2L14-ETV6</i> is most frequently detected in the mesenchymal entity, accounting for ∼19% of these tumors. Ectopic expression of BCL2L14<i>-</i>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<i>-</i>ETV6 fusions prime partial epithelial<i>-</i>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 <i>BCL2L14-ETV6</i> as a recurrent gene fusion in more aggressive form of TNBC tumors.