Expressed gene fusions as frequent drivers of poor outcomes in hormone receptor–positive breast cancer
Por:
Matissek K.J., Onozato M.L., Sun S., Zheng Z., Schultz A., Lee J., Patel K., Jerevall P.-L., Saladi S.V., Macleay A., Tavallai M., Badovinac-Crnjevic T., Barrios C., BeÅŸe N., Chan A., Chavarri-Guerra Y., Debiasi M., Demirdogen E., Egeli U., Gokgoz S., Gomez H., Liedke P., Tasdelen I., Tolunay S., Werutsky G., Louis J.S., Horick N., Finkelstein D.M., Le L.P., Bardia A., Goss P.E., Sgroi D.C., Iafrate A.J., Ellisen L.W.
Publicada:
1 ene 2018
Categoría:
Oncology
Resumen:
We sought to uncover genetic drivers of hormone receptor–positive (HR +) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identifi ed intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR + breast cancer. FISH confi rmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in threedimensional culture, whereas expression in HR + breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR + breast cancer. Collectively, our fi ndings identify expressed gene fusions as frequent and potentially actionable drivers in HR + breast cancer. SIGNIFICANCE: By using a powerful clinical molecular diagnostic assay, we identifi ed expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR + breast cancer. The prevalence and biological and prognostic signifi cance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. © 2018 American Association for Cancer Research.
Filiaciones:
Matissek K.J.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Onozato M.L.:
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Sun S.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Zheng Z.:
Harvard Medical School, Boston, MA, United States
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Schultz A.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Lee J.:
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Patel K.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Jerevall P.-L.:
Harvard Medical School, Boston, MA, United States
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Saladi S.V.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Macleay A.:
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Tavallai M.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Badovinac-Crnjevic T.:
University Hospital Zagreb, Zagreb, Croatia
Barrios C.:
Latin America Cooperative Oncology Group (LACOG) and Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
Chan A.:
Mount Hospital, Perth, Australia
Chavarri-Guerra Y.:
Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubiran, D.F., México City, Mexico
Debiasi M.:
Latin America Cooperative Oncology Group (LACOG) and Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
Demirdogen E.:
Departments of Medical Biology, General Surgery, Pathology of Medical Faculty of Uludag University, Bursa, Turkey
Egeli U.:
Departments of Medical Biology, General Surgery, Pathology of Medical Faculty of Uludag University, Bursa, Turkey
Gokgoz S.:
Departments of Medical Biology, General Surgery, Pathology of Medical Faculty of Uludag University, Bursa, Turkey
Gomez H.:
Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Liedke P.:
Latin America Cooperative Oncology Group (LACOG) and Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
Tasdelen I.:
Departments of Medical Biology, General Surgery, Pathology of Medical Faculty of Uludag University, Bursa, Turkey
Tolunay S.:
Departments of Medical Biology, General Surgery, Pathology of Medical Faculty of Uludag University, Bursa, Turkey
Werutsky G.:
Latin America Cooperative Oncology Group (LACOG) and Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
Louis J.S.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Horick N.:
Biostatistics Center, Massachusetts General Hospital, Boston, MA, United States
Finkelstein D.M.:
Harvard Medical School, Boston, MA, United States
Biostatistics Center, Massachusetts General Hospital, Boston, MA, United States
Le L.P.:
Harvard Medical School, Boston, MA, United States
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Bardia A.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Goss P.E.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Sgroi D.C.:
Harvard Medical School, Boston, MA, United States
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Iafrate A.J.:
Harvard Medical School, Boston, MA, United States
Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
Ellisen L.W.:
Massachusetts General Hospital Cancer Center, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Department of Radiation Oncology, Acibadem Breast Research Institute, Istanbul, Turkey
Bronze
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