融合伙伴的故事系列丨无意苦争春,一任群芳妒:FGFR融合基因融合谱的故事

肺癌丨精准医疗,FGFR异常靶向治疗新突破
成纤维样长因子受体(FGFR)是一类跨膜酪氨酸激酶受体(transmembrane receptortyrosine kinase, RTK),其家族包括4个FGFR受体亚型,FGFR1-4,多达18个FGF生长因子配体。FGFR1-4在成人体内起着更重要的生理功能,包括组织、代谢平衡、内分泌、血管生成、伤口愈合等[1, 2]。FGFR 基因融合可使激酶区活化从而诱导多种肿瘤的形成和发展[3, 4]。而靶向于FGFR融合基因的小分子抑制剂可明显抑制肿瘤发生[5-8]。FGFR1的融合比较少见,更主要的致癌因素是过量表达。FGFR2的融合主要集中在胆管癌。FGFR3 融合主要发生在神经胶质瘤,其次是膀胱癌。FGFR4的融合则更少见。
2017年5月,《Nat Med》杂志发表一篇重量级文章,纪念MSKCC癌症研究中心的科学家采用MSK-IMPACT方法,开展了一项大规模、前瞻性的临床测序研究,他们对1万多名晚期癌症患者,接近300多种肿瘤进行基因二代测序,同时收集这些患者的临床注释、病理等方面的信息,其中FGFR融合69例,其中FGFR1融合4例,结直肠癌2例占0.20%(2/978),融合伙伴为CLVS1-RAB11FIP1-,前列腺癌1例占0.16%(1/621),融合伙伴为ACPP-和非小细胞肺癌1例占0.06%(1/1563),融合伙伴为TACC1-;FGFR2融合34例,胆管癌25例占10.46%(25/239),融合伙伴BICC1-为7例占28.00%(7/25),KIAA1217-为2例占8.00%(2/25),AHCYL1-RASAL2-TACC2-FAM13C-TFEC-,ROCK1-NRBF2-NRAP-PHC1-REEP3-LAMC1-RABGAP1L-CTNNA3-SHC2-RAB7L1-NOL4-各1例占4.00%(1/25),胰腺癌3例占0.62%(3/483),融合伙伴分别为KIAA1217-VCL-MYOF-,膀胱癌1例占0.25%(1/405),融合伙伴为MARVELD3-,乳腺癌1例占0.08%(1/1238),融合伙伴为BET1-,小肠肿瘤1例占3.03%(1/33),非小细胞肺癌1例占0.06%(1/1563),融合伙伴为KLRAQ1-和原发灶不明肿瘤2例,融合伙伴分别为KIF14-KCNH7-;FGFR3融合29例,胶质瘤13例占2.54%(13/512),融合伙伴TACC3-为12例占92.31%(12/13),ST7L-为1例占7.69%(1/13),膀胱癌6例占1.48%(6/405),融合伙伴TACC3-为4例占66.67%(4/6),JAKMIP1-为1例占16.67%(1/6),TNIP2-为1例占16.67%(1/6),非小细胞肺癌5例占0.32%(5/1563),融合伙伴TACC3-为4例占80.00%(4/5),CXorf26-为1例占20.00%(1/5),生殖细胞肿瘤1例占0.36%(1/236),融合伙伴为TACC3-,子宫内膜癌1例占0.48%(1/210),融合伙伴为TACC3-,头颈部肿瘤1例占0.60%(1/166),融合伙伴为TACC3-,前列腺癌1例占0.16%(1/621),融合伙伴为C4orf48-和乳腺癌1例占0.08%(1/1238),融合伙伴为WHSC1-;FGFR4融合2例,非小细胞肺癌1例占0.06%(1/1563),融合伙伴为SLIT3-,宫颈癌1例占2.17%(1/46),融合伙伴为ZNF346-[9]。
2019年Qin等[10]在《J ThoracOncol》报道采用二代捕获测序技术在26054例非小细胞肺癌中FGFR融合阳性率为0.20%(52/26054),包括1例FGFR1融合,融合伙伴为BCL2-;10例FGFR2融合,融合伙伴为KIAA1598-(2例),CIT-(2例),LZTFL1-(1例),ERC1-(1例),POC1B-(1例),SORBS1-(1例),TP73-(1例)和TXLNA-(1例);39例FGFR3融合,融合伙伴为TACC3-(37例),PHLDB3-(1例)和WHSC1-(1例);2例FGFR4融合,融合伙伴为NSD1-ANO3-
评述
FGFR是一种跨膜酪氨酸激酶受体,广泛存在于正常细胞。它通过与成纤维细胞生长因子配体结合发生二聚体化、自磷酸化,进一步激活下游信号通路如MAPK、PI3K/AKT/mTOR、JNK/STAT等,调控细胞增殖、分化、迁移及血管生成等[11]。
Wu等[8]对数种实体肿瘤进行基因测序,首次发现肝内胆管细胞癌中存在FGFR2 融合基因。肝内胆管细胞癌患者中FGFR2融合基因的检出率约为13.6%-45.0%,已发现的融合类型有FGFR2-BICC1FGFR2-PPHLN1FGFR2-MGEA5FGFR2-TACC3AHCYL1-FGFR2FGFR2-KIAA1217RASAL2-FGFR2TACC2-FGFR2FGFR2-FAM13CTFEC-FGFR2FGFR2-ROCK1FGFR2-NRBF2FGFR2-NRAPFGFR2-PHC1FGFR2-REEP3LAMC1-FGFR2RABGAP1L-FGFR2FGFR2-CTNNA3FGFR2-SHC2RAB7L1-FGFR2FGFR2-NOL4FGFR2-CCDC6等[8, 9, 12-16]。值得注意的是,FGFR2 融合基因均出现在肝内胆管细胞癌患者中,而在肝细胞肝癌及肝外胆管细胞癌中没有发现,这提示FGFR2基因融合可能是肝内胆管细胞癌特征性的遗传学改变[14, 15]。
神经胶质瘤FGFR3融合方面,Linzey等[17]在一例儿童丘脑或中央型少突胶质细胞瘤中发现新型的FGFR3-PHGDH,至此神经胶质瘤已发现的FGFR3融合类型有FGFR3-TACC3ST7L-FGFR3FGFR3-CAMK2A等[9, 18];膀胱癌FGFR3融合方面,Vandekerkhove等[19] 在循环肿瘤DNA揭示膀胱癌融合谱方面发现新型的FGFR3-ADD1,至此膀胱癌已发现的FGFR3融合类型有FGFR3-TACC3JAKMIP1-FGFR3TNIP2-FGFR3FGFR3-BAIAP2L1等[8, 9, 20]。
MSKCC最新的有关FGFR的融合的数据给接下来的FGFR临床试验提供了很好的突破点。即胆管癌的FGFR2 融合、神经胶质瘤及膀胱癌的FGFR3融合等。以前的临床试验结果也显示,FGFR融合突变的应答效率是最高的。因此希望FGFR-TKI能够早日得到积极临床数据,获得FDA批准,给患者带来积极的获益。

参考文献

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