Schulten Hans-Juergen, Alotibi Reem, Al-Ahmadi Alaa, Ata Manar, Karim Sajjad, Huwait Etimad, Gari Mamdooh, Al-Ghamdi Khalid, Al-Mashat Faisal, Al-Hamour Osman, Al-Qahtani Mohammad Hussain, Al-Maghrabi Jaudah
BMC Genomics. 2015;16 Suppl 1(Suppl 1):S6. doi: 10.1186/1471-2164-16-S1-S6. Epub 2015 Jan 15.
Whereas 40 % to 70 % of papillary thyroid carcinomas (PTCs) are characterized by a BRAF mutation (BRAFmut), unified biomarkers for the genetically heterogeneous group of BRAF wild type (BRAFwt) PTCs are not established yet. Using state-of-the-art technology we compared RNA expression profiles between conventional BRAFwt and BRAFmut PTCs.
Microarrays covering 36,079 reference sequences were used to generate whole transcript expression profiles in 11 BRAFwt PTCs including five micro PTCs, 14 BRAFmut PTCs, and 7 normal thyroid specimens. A p-value with a false discovery rate (FDR) < 0.05 and a fold change > 2 were used as a threshold of significance for differential expression. Network and pathway utilities were employed to interpret significance of expression data. BRAF mutational status was established by direct sequencing the hotspot region of exon 15.
We identified 237 annotated genes that were significantly differentially expressed between BRAFwt and BRAFmut PTCs. Of these, 110 genes were down- and 127 were upregulated in BRAFwt compared to BRAFmut PTCs. A number of molecules involved in thyroid hormone metabolism including thyroid peroxidase (TPO) were differentially expressed between both groups. Among cancer-associated molecules were ERBB3 that was downregulated and ERBB4 that was upregulated in BRAFwt PTCs. Two microRNAs were significantly differentially expressed of which miR492 bears predicted functions relevant to thyroid-specific molecules. The protein kinase A (PKA) and the G protein-coupled receptor pathways were identified as significantly related signaling cascades to the gene set of 237 genes. Furthermore, a network of interacting molecules was predicted on basis of the differentially expressed gene set.
The expression study focusing on affected genes that are differentially expressed between BRAFwt and BRAFmut conventional PTCs identified a number of molecules which are connected in a network and affect important canonical pathways. The identified gene set adds to our understanding of the tumor biology of BRAFwt and BRAFmut PTCs and contains genes/biomarkers of interest.
虽然40%至70%的甲状腺乳头状癌（PTC）具有BRAF突变（BRAFmut）特征，但尚未建立针对BRAF野生型（BRAFwt）PTC这种基因异质性群体的统一生物标志物。我们使用最先进的技术比较了传统BRAFwt和BRAFmut PTC之间的RNA表达谱。
使用覆盖36,079个参考序列的微阵列来生成11个BRAFwt PTC（包括5个微小PTC）、14个BRAFmut PTC和7个正常甲状腺标本的全转录本表达谱。将错误发现率（FDR）<0.05且倍数变化>2的p值用作差异表达的显著性阈值。利用网络和通路工具来解释表达数据的意义。通过直接对第15外显子的热点区域进行测序来确定BRAF突变状态。
我们鉴定出237个注释基因在BRAFwt和BRAFmut PTC之间存在显著差异表达。其中，与BRAFmut PTC相比，BRAFwt中有110个基因下调，127个基因上调。两组之间一些参与甲状腺激素代谢的分子（包括甲状腺过氧化物酶（TPO））存在差异表达。在癌症相关分子中，ERBB3在BRAFwt PTC中下调，ERBB4上调。有两个微小RNA存在显著差异表达，其中miR492具有与甲状腺特异性分子相关的预测功能。蛋白激酶A（PKA）和G蛋白偶联受体途径被确定为与这237个基因的基因集显著相关的信号级联。此外，基于差异表达基因集预测了一个相互作用分子网络。
聚焦于BRAFwt和BRAFmut传统PTC之间差异表达的受影响基因的表达研究鉴定出了一些在网络中相互连接并影响重要经典通路的分子。所鉴定的基因集增进了我们对BRAFwt和BRAFmut PTC肿瘤生物学的理解，并包含了有意义的基因/生物标志物。
