Neerincx M, Sie D L S, van de Wiel M A, van Grieken N C T, Burggraaf J D, Dekker H, Eijk P P, Ylstra B, Verhoef C, Meijer G A, Buffart T E, Verheul H M W
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Oncogenesis. 2015 Oct 5;4(10):e170. doi: 10.1038/oncsis.2015.29.
MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) <0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR <0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC.
微小RNA（miRs）已被公认为是很有前景的生物标志物。目前尚不清楚肿瘤来源的miRs在原发性结直肠癌（pCRC）和转移病灶之间的差异表达程度，以及肿瘤组织与周围正常组织的表达谱差异程度。对220份新鲜冷冻样本进行的二代测序（NGS），包括来自38例患者的配对原发性和转移性肿瘤组织以及非肿瘤组织，结果显示有2245个已知的独特成熟miRs和515个新的候选miRs表达。pCRC组织与配对转移灶的miR表达谱进行无监督聚类并不能区分这两个实体，而pCRC与正常结直肠黏膜的miR表达谱进行无监督聚类则显示肿瘤样本与其配对的正常黏膜完全分开。222个miRs能够区分pCRC和转移灶与正常组织样本（错误发现率（FDR）<0.05）。表达量最高的肿瘤特异性miRs是miR-21和miR-92a，二者此前均被描述与结直肠癌有关，有作为早期检测循环生物标志物的潜力。在pCRC与相应转移灶之间，只有8个miRs（占分析的miR转录组的0.5%）存在差异表达（FDR<0.1），包括5个已知miRs（miR-320b、miR-320d、miR-3117、miR-1246和miR-663b）和3个新的候选miRs（chr 1-2552-5p、chr 8-20656-5p和chr 10-25333-3p）。这些结果表明，利用NGS鉴定出了在晚期结直肠癌中表达的此前未被识别的候选miRs。此外，pCRC和转移病灶的miR表达谱具有高度可比性，对于晚期结直肠癌患者的预后或治疗反应可能具有相似的预测价值。
