Slattery Martha L, Herrick Jennifer S, Mullany Lila E, Wolff Erica, Hoffman Michael D, Pellatt Daniel F, Stevens John R, Wolff Roger K
Department of Medicine, University of Utah, Salt Lake City, UT, USA.
Department of Mathematics and Statistics, Utah State University, Logan, UT, USA.
Mod Pathol. 2016 Aug;29(8):915-27. doi: 10.1038/modpathol.2016.73. Epub 2016 May 20.
MiRNAs regulate gene expression by post-transcriptionally suppressing mRNA translation or by causing mRNA degradation. It has been proposed that unique miRNAs influence specific tumor molecular phenotype. In this paper, we test the hypotheses that miRNA expression differs by tumor molecular phenotype and that those differences may influence prognosis. Data come from population-based studies of colorectal cancer conducted in Utah and the Northern California Kaiser Permanente Medical Care Program. A total of 1893 carcinoma samples were run on the Agilent Human miRNA Microarray V19.0 containing 2006 miRNAs. We assessed differences in miRNA expression between TP53-mutated and non-mutated, KRAS-mutated and non-mutated, BRAF-mutated and non-mutated, CpG island methylator phenotype (CIMP) high and CIMP low, and microsatellite instability (MSI) and microsatellite stable (MSS) colon and rectal tumors. Using a Cox proportional hazard model we evaluated if those miRNAs differentially expressed by tumor phenotype influenced survival after adjusting for age, sex, and AJCC stage. There were 22 differentially expressed miRNAs for TP53-mutated colon tumors and 5 for TP53-mutated rectal tumors with a fold change of >1.49 (or <0.67). Additionally, 13 miRNAS were differentially expressed for KRAS-mutated rectal tumors, 8 differentially expressed miRNAs for colon CIMP high tumors, and 2 differentially expressed miRNAs for BRAF-mutated colon tumors. The majority of differentially expressed miRNAS were observed between MSI and MSS tumors (94 differentially expressed miRNAs for colon; 41 differentially expressed miRNAs for rectal tumors). Of these miRNAs differentially expressed between MSI and MSS tumors, the majority were downregulated. Ten of the differentially expressed miRNAs were associated with survival; after adjustment for MSI status, five miRNAS, miR-196b-5p, miR-31-5p, miR-99b-5p, miR-636, and miR-192-3p, were significantly associated with survival. In summary, it appears that the majority of miRNAs that are differentially expressed by tumor molecular phenotype are MSI tumors. However, these miRNAs appear to have minimal effect on prognosis.
微小RNA（miRNAs）通过转录后抑制mRNA翻译或导致mRNA降解来调控基因表达。有人提出，独特的miRNAs会影响特定的肿瘤分子表型。在本文中，我们检验了以下假设：miRNA表达因肿瘤分子表型而异，且这些差异可能影响预后。数据来自于在犹他州和北加利福尼亚凯撒永久医疗保健计划中开展的基于人群的结直肠癌研究。总共1893份癌组织样本在包含2006种miRNAs的安捷伦人类miRNA微阵列V19.0上进行检测。我们评估了TP53突变与未突变、KRAS突变与未突变、BRAF突变与未突变、CpG岛甲基化表型（CIMP）高与CIMP低以及微卫星不稳定性（MSI）和微卫星稳定（MSS）的结肠和直肠肿瘤之间miRNA表达的差异。使用Cox比例风险模型，我们评估了那些因肿瘤表型而差异表达的miRNAs在调整年龄、性别和美国癌症联合委员会（AJCC）分期后是否影响生存。TP53突变的结肠肿瘤中有22种差异表达的miRNAs，TP53突变的直肠肿瘤中有5种差异表达的miRNAs，其变化倍数>1.49（或<0.67）。此外，KRAS突变的直肠肿瘤中有13种miRNAs差异表达，CIMP高的结肠肿瘤中有8种差异表达的miRNAs，BRAF突变的结肠肿瘤中有2种差异表达的miRNAs。大多数差异表达的miRNAs是在MSI和MSS肿瘤之间观察到的（结肠中有94种差异表达的miRNAs；直肠肿瘤中有41种差异表达的miRNAs）。在MSI和MSS肿瘤之间差异表达的这些miRNAs中，大多数是下调的。10种差异表达的miRNAs与生存相关；在调整MSI状态后，5种miRNAs，即miR-196b-5p、miR-31-5p、miR-99b-5p、miR-636和miR-192-3p，与生存显著相关。总之，似乎因肿瘤分子表型而差异表达的大多数miRNAs是MSI肿瘤中的。然而，这些miRNAs似乎对预后影响极小。
