Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor–Positive Breast Cancer,Cancer Discovery

当前位置： X-MOL 学术 › Cancer Discov. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor–Positive Breast Cancer
Cancer Discovery ( IF 28.2 ) Pub Date : 2018-03-01 , DOI: 10.1158/2159-8290.cd-17-0535
Karina J Matissek _{1,

2} , Maristela L Onozato ₃ , Sheng Sun _{1,

2} , Zongli Zheng _{2,

3,

4} , Andrew Schultz ₁ , Jesse Lee ₃ , Kristofer Patel ₁ , Piiha-Lotta Jerevall _{2,

3} , Srinivas Vinod Saladi _{1,

2} , Allison Macleay ₃ , Mehrad Tavallai _{1,

2} , Tanja Badovinac-Crnjevic ₅ , Carlos Barrios ₆ , Nuran Beşe ₇ , Arlene Chan ₈ , Yanin Chavarri-Guerra ₉ , Marcio Debiasi ₆ , Elif Demirdögen ₁₀ , Ünal Egeli ₁₀ , Sahsuvar Gökgöz ₁₀ , Henry Gomez ₁₁ , Pedro Liedke ₆ , Ismet Tasdelen ₁₀ , Sahsine Tolunay ₁₀ , Gustavo Werutsky ₆ , Jessica St Louis ₁ , Nora Horick ₁₂ , Dianne M Finkelstein _{2,

12} , Long Phi Le _{2,

3} , Aditya Bardia _{1,

2} , Paul E Goss _{1,

2} , Dennis C Sgroi _{2,

3} , A John Iafrate _{2,

3} , Leif W Ellisen _{1,

2}

Affiliation

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
University Hospital Zagreb, Zagreb, Croatia.
Latin America Cooperative Oncology Group (LACOG) and Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
Department of Radiation Oncology, Acibadem Breast Research Institute, Istanbul, Turkey.
Mount Hospital, Perth, Australia.
Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubiran, México City D.F., México.
Departments of Medical Biology, General Surgery, Pathology of Medical Faculty of Uludag University, Bursa, Turkey.
Instituto Nacional de Enfermedades Neoplasicas, Lima, Perú.
Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.

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. 272.

See related article by Liu et al., p. 354.

This article is highlighted in the In This Issue feature, p. 253

中文翻译：

表达基因融合是激素受体阳性乳腺癌预后不良的常见驱动因素

我们试图揭示激素受体阳性 (HR ⁺ ) 乳腺癌的遗传驱动因素，使用靶向下一代测序方法检测表达的基因重排，而无需事先了解融合伙伴。我们在 14% (24/173) 的未选择的晚期 HR ⁺乳腺癌患者中鉴定了涉及驱动基因的基因间融合，包括PIK3CA、AKT3、RAF1和ESR1。FISH 证实了原发性和转移性肿瘤中相应的染色体重排。新型激酶融合蛋白在非转化细胞中的表达解除了磷蛋白信号传导、细胞增殖和三维培养中的存活率，而在 HR ⁺乳腺癌模型在体外和体内调节雌激素依赖性生长并赋予激素治疗抗性。引人注目的是，在重排阳性与重排阴性肿瘤患者中观察到更短的总生存期。相应地，在 300 名原发性 HR ⁺乳腺癌患者中，融合并不常见 (<5%) 。总的来说，我们的研究结果将表达的基因融合确定为 HR ⁺乳腺癌中常见且可能可行的驱动因素。