Lehtinen Birgitta, Raita Annina, Kesseli Juha, Annala Matti, Nordfors Kristiina, Yli-Harja Olli, Zhang Wei, Visakorpi Tapio, Nykter Matti, Haapasalo Hannu, Granberg Kirsi J
BioMediTech Institute and Faculty of Medicine and Life Sciences, Biokatu 8, 33520, Tampere, Finland.
Fimlab Laboratories Ltd., Tampere University Hospital, Biokatu 4, 33520, Tampere, Finland.
BMC Cancer. 2017 May 3;17(1):310. doi: 10.1186/s12885-017-3274-9.
Fibroblast growth factor receptors (FGFRs) are well-known proto-oncogenes in several human malignancies and are currently therapeutically targeted in clinical trials. Among glioma subtypes, activating FGFR1 alterations have been observed in a subpopulation of pilocytic astrocytomas while FGFR3 fusions occur in IDH wild-type diffuse gliomas, resulting in high FGFR3 protein expression. The purpose of this study was to associate FGFR1 and FGFR3 protein levels with clinical features and genetic alterations in ependymoma and pilocytic astrocytoma.
FGFR1 and FGFR3 expression levels were detected in ependymoma and pilocytic astrocytoma tissues using immunohistochemistry. Selected cases were further analyzed using targeted sequencing.
Expression of both FGFR1 and FGFR3 varied within all tumor types. In ependymomas, increased FGFR3 or FGFR1 expression was associated with high tumor grade, cerebral location, young patient age, and poor prognosis. Moderate-to-strong expression of FGFR1 and/or FGFR3 was observed in 76% of cerebral ependymomas. Cases with moderate-to-strong expression of both proteins had poor clinical prognosis. In pilocytic astrocytomas, moderate-to-strong FGFR3 expression was detected predominantly in non-pediatric patients. Targeted sequencing of 12 tumors found no protein-altering mutations or fusions in FGFR1 or FGFR3.
Elevated FGFR3 and FGFR1 protein expression is common in aggressive ependymomas but likely not driven by genetic alterations. Further studies are warranted to evaluate whether ependymoma patients with high FGFR3 and/or FGFR1 expression could benefit from treatment with FGFR inhibitor based therapeutic approaches currently under evaluation in clinical trials.
成纤维细胞生长因子受体（FGFRs）是几种人类恶性肿瘤中著名的原癌基因，目前在临床试验中作为治疗靶点。在胶质瘤亚型中，在一部分毛细胞型星形细胞瘤中观察到激活的FGFR1改变，而FGFR3融合发生在异柠檬酸脱氢酶（IDH）野生型弥漫性胶质瘤中，导致FGFR3蛋白高表达。本研究的目的是将FGFR1和FGFR3蛋白水平与室管膜瘤和毛细胞型星形细胞瘤的临床特征及基因改变相关联。
采用免疫组织化学法检测室管膜瘤和毛细胞型星形细胞瘤组织中FGFR1和FGFR3的表达水平。对选定病例进一步进行靶向测序分析。
在所有肿瘤类型中，FGFR1和FGFR3的表达均有所不同。在室管膜瘤中，FGFR3或FGFR1表达增加与肿瘤分级高、位于脑内、患者年龄小及预后差相关。76%的脑室内管膜瘤观察到FGFR1和/或FGFR3中度至强表达。两种蛋白均为中度至强表达的病例临床预后较差。在毛细胞型星形细胞瘤中，FGFR3中度至强表达主要在非儿童患者中检测到。对12例肿瘤进行靶向测序未发现FGFR1或FGFR3有蛋白质改变的突变或融合。
FGFR3和FGFR1蛋白表达升高在侵袭性室管膜瘤中常见，但可能不是由基因改变驱动。有必要进一步研究评估FGFR3和/或FGFR1表达高的室管膜瘤患者是否能从目前临床试验中正在评估的基于FGFR抑制剂的治疗方法中获益。
