Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma.
Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma.
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DOI：
10.1038/srep44653
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发表时间：
2017-03-17
影响因子：
4.6
通讯作者：
Sethupathy P
中科院分区：
文献类型：
--
作者：
Dinh TA;Vitucci EC;Wauthier E;Graham RP;Pitman WA;Oikawa T;Chen M;Silva GO;Greene KG;Torbenson MS;Reid LM;Sethupathy P
纤维板层癌（FLC）是一种独特的肝癌，主要影响年轻人，其特征是DNAJB 1和PRKACA之间的融合事件。通过分析来自癌症基因组图谱（TCGA）的约30种癌症类型的> 9，100种肿瘤的RNA测序数据，我们表明DNAJB 1-PRKACA融合对FLC具有特异性。我们证明，FLC肿瘤（n = 6）表现出不同的信使RNA（mRNA）和长的基因间非编码RNA（lincRNA）的配置文件相比，肝细胞癌（n = 263）和胆管癌（n = 36），两个最常见的肝癌。我们还鉴定了一组mRNA（n = 16）和lincRNA（n = 4），包括LINC 00473，其将FLC与约25种其他肝癌和非肝癌类型区分开来。我们通过分析两个独立的FLC队列（n = 20和34）证实了这种独特的FLC特征。最后，我们通过蛋白质印迹和免疫组织化学在蛋白质水平上验证FLC签名中的一个特定基因碳酸酐酶XII（CA 12）的过表达。mRNA和lincRNA特征都支持蛋白激酶A（PKA）信号传导在塑造FLC基因表达景观中的主要作用，并提出了值得进一步研究的新的候选FLC癌基因。
Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.