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

Menée à partir de données de séquençage du génome entier de 215 tumeurs mammaires et de l'analyse de réarrangements de gènes adjacents, cette étude met en évidence la présence de gènes de fusion BCL2L14-ETV6 dans les formes les plus agressives du cancer du sein triple négatif

Résumé en anglais

Identification of triple-negative breast cancer (TNBC)-specific genetic events that could guide the treatment decisions represents an unmet clinical need, whereas recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations. In this study, analysis of whole-genome sequencing data for 215 breast tumors catalogued 99 recurrent gene fusions. Among different types of rearrangements, we found that a special class of cryptic adjacent gene rearrangements (AGRs) may occur more frequently than realized in breast cancer. The most frequent AGRs are preferentially found in more aggressive forms of breast cancers, among which BCL2L14–ETV6 is exclusively detected in TNBC. BCL2L14–ETV6 is enriched in high-grade, necrotic, mesenchymal TNBC tumors, and endows increased invasiveness and paclitaxel resistance via inducing partial epithelial mesenchymal transition.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