Michigan Center for Translational Pathology, University of Michigan Medical School, 1400 E. Medical Center Drive 5316 CCGC, Ann Arbor, MI 48109-5940, USA.
Cancer Discov. 2013 Jun;3(6):636-47. doi: 10.1158/2159-8290.CD-13-0050. Epub 2013 Apr 4.
Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types.
通过一项针对晚期癌症的前瞻性临床测序计划，我们确定了四个存在 FGFR2 基因重排的索引病例，包括胆管癌、乳腺癌和前列腺癌患者。在对多个肿瘤队列的 FGFR 重排进行扩展评估后，我们在肺鳞状细胞癌、膀胱癌、甲状腺癌、口腔癌、胶质母细胞瘤和头颈部鳞状细胞癌中发现了具有完整激酶结构域的其他 FGFR 融合。所有测试的 FGFR 融合伙伴均表现出寡聚化能力，提示存在一种共享的激酶激活模式。FGFR 融合蛋白的过表达可诱导细胞增殖。两种携带 FGFR3 融合蛋白的膀胱癌细胞系在体外和体内均表现出对药物抑制的敏感性增强。由于 FGFR 家族融合与多种寡聚化伙伴的组合可能性，包含基因融合转录组分析的临床测序工作有望在多种癌症类型中识别出罕见的、可靶向的 FGFR 融合。
