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Cancer Discov. 2018 Mar;8(3):336-353. doi: 10.1158/2159-8290.CD-17-0535. Epub 2017 Dec 14.

Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor-Positive Breast Cancer.

Author information

1
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2
Harvard Medical School, Boston, Massachusetts.
3
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
4
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
5
University Hospital Zagreb, Zagreb, Croatia.
6
Latin America Cooperative Oncology Group (LACOG) and Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
7
Department of Radiation Oncology, Acibadem Breast Research Institute, Istanbul, Turkey.
8
Mount Hospital, Perth, Australia.
9
Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubiran, México City D.F., México.
10
Departments of Medical Biology, General Surgery, Pathology of Medical Faculty of Uludag University, Bursa, Turkey.
11
Instituto Nacional de Enfermedades Neoplasicas, Lima, Perú.
12
Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.
13
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. lellisen@mgh.harvard.edu.
#
Contributed equally

Abstract

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 identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed 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 three-dimensional 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 findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336-53. ©2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Liu et al., p. 354This article is highlighted in the In This Issue feature, p. 253.

PMID:
29242214
DOI:
10.1158/2159-8290.CD-17-0535
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