Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas.
Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas.
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DOI：
10.1158/1078-0432.ccr-12-3708
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发表时间：
2013-05-01
期刊：
影响因子：
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通讯作者：
Yao J
中科院分区：
文献类型：
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作者：
Zhao Q;Caballero OL;Davis ID;Jonasch E;Tamboli P;Yung WK;Weinstein JN;Kenna Shaw for TCGA research network;Strausberg RL;Yao J
我们的目标是确定肿瘤特异性的选择性剪接事件在早期检测，诊断，预后和治疗癌症的潜在应用。我们分析了470例透明细胞肾细胞癌（ccRCC）和68例肾组织的RNA-seq数据，以确定肿瘤特异性选择性剪接事件。我们进一步关注FGFR 2亚型转换，并通过使用来自多个平台和肿瘤类型的基因组数据的综合分析来表征表达不同FGFR 2亚型的ccRCC。我们在ccRCC中鉴定了113个最佳候选选择性剪接基因。显著地，在近90%的ccRCC中，FGFR 2基因转录物从正常的IIIb同种型（“上皮”）转换为IIIc同种型（“间充质”）。这种转换是肾脏特异性的，因为它很少在其他癌症中观察到。FGFR 2-IIIb ccRCC显示类似于来自正常肾脏的转录组和甲基化组，而FGFR 2-IIIc ccRCC具有升高的低氧和间充质表达特征。临床上，FGFR 2-IIIb ccRCC尺寸较小，肿瘤分级较低，并且与较长的患者生存期相关。基因集富集和DNA拷贝数分析表明，FGFR 2-IIIb ccRCC与肾嗜酸细胞瘤和嫌色细胞RCC密切相关。病理学家对肿瘤组织学的重新检查将FGFR 2-IIIb肿瘤鉴定为嫌色细胞RCC和透明细胞乳头状RCC。FGFR 2 IIIb RCC代表误诊的ccRCC病例，表明FGFR 2亚型检测可用于RCC亚型的诊断。以组织特异性方式发现FGFR 2的普遍亚型转换为未来开发FGFR 2-IIIc作为ccRCC的独特早期检测生物标志物和治疗靶标提供了希望。
We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy of cancers. We analyzed RNA-seq data on 470 clear cell renal cell carcinomas (ccRCC) and 68 kidney tissues to identify tumor-specific alternative splicing events. We further focused on the FGFR2 isoform switch and characterized ccRCCs expressing different FGFR2 isoforms by integrated analyses using genomic data from multiple platforms and tumor types. We identified 113 top candidate alternatively spliced genes in ccRCC. Prominently, the FGFR2 gene transcript switched from the normal IIIb isoform (“epithelial”) to IIIc isoform (“mesenchymal”) in nearly 90% of ccRCCs. This switch is kidney-specific since it was rarely observed in other cancers. The FGFR2-IIIb ccRCCs show a transcriptome and methylome resembling those from normal kidney, whereas FGFR2-IIIc ccRCCs possess elevated hypoxic and mesenchymal expression signatures. Clinically, FGFR2-IIIb ccRCCs are smaller in size, of lower tumor grade, and associated with longer patient survival. Gene set enrichment and DNA copy number analyses indicated that FGFR2-IIIb ccRCCs are closely associated with renal oncocytomas and chromophobe RCCs. A re-examination of tumor histology by pathologists identified FGFR2-IIIb tumors as chromophobe RCCs and clear cell papillary RCCs. FGFR2 IIIb RCCs represent mis-diagnosed ccRCC cases, suggesting FGFR2 isoform testing can be used in the diagnosis of RCC subtypes. The finding of a prevalent isoform switch of FGFR2 in a tissue-specific manner holds promise for the future development of FGFR2-IIIc as a distinct early detection biomarker and therapeutic target for ccRCC.