Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
Rutgers University, Piscataway, NJ, 08854, USA.
Nat Commun. 2018 Nov 16;9(1):4821. doi: 10.1038/s41467-018-07341-4.
Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.
在甲状腺癌和肺癌中观察到涉及致癌基因 RET 的融合。在这里，我们报告了乳腺癌中 RET 基因的改变，包括扩增、错义突变、已知融合、新融合和重排。描述了它们在乳腺癌中的频率、致癌潜能和可操作性。对 8 个 RET 融合中的 2 个（NCOA4-RET 和一种新型 RASGEF1A-RET 融合）和 RET 扩增进行了功能表征，并证明它们能够激活 RET 激酶并通过 MAPK 和 PI3K 途径驱动信号转导。这些融合和 RET 扩增可诱导非肿瘤细胞转化，支持异种移植物肿瘤形成，并对 RET 抑制敏感。在进展性 HER2 靶向治疗的转移性乳腺癌的指数病例中发现了 NCOA4-RET 融合。随后用 RET 抑制剂卡博替尼治疗导致快速的临床和影像学反应。通过基因组分析鉴定的 RET 改变是很有前途的治疗靶点，存在于一部分乳腺癌中。
