Landscape analysis of adjacent gene rearrangements reveals BCL2L14-ETV6 gene fusions in more aggressive triple-negative breast cancer.
Proc Natl Acad Sci U S A
; 117(18): 9912-9921, 2020 05 05.
Article
em En
| MEDLINE
| ID: mdl-32321829
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, 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 â¼19% 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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Rearranjo Gênico
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Proteínas Proto-Oncogênicas c-bcl-2
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Proteínas Proto-Oncogênicas c-ets
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Neoplasias de Mama Triplo Negativas
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article