Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America.
PLoS One. 2011;6(10):e25451. doi: 10.1371/journal.pone.0025451. Epub 2011 Oct 5.
Despite recent discoveries of new molecular targets and pathways, the search for an effective therapy for Glioblastoma Multiforme (GBM) continues. A newly emerged field, radiogenomics, links gene expression profiles with MRI phenotypes. MRI-FLAIR is a noninvasive diagnostic modality and was previously found to correlate with cellular invasion in GBM. Thus, our radiogenomic screen has the potential to reveal novel molecular determinants of invasion. Here, we present the first comprehensive radiogenomic analysis using quantitative MRI volumetrics and large-scale gene- and microRNA expression profiling in GBM.
Based on The Cancer Genome Atlas (TCGA), discovery and validation sets with gene, microRNA, and quantitative MR-imaging data were created. Top concordant genes and microRNAs correlated with high FLAIR volumes from both sets were further characterized by Kaplan Meier survival statistics, microRNA-gene correlation analyses, and GBM molecular subtype-specific distribution.
The top upregulated gene in both the discovery (4 fold) and validation (11 fold) sets was PERIOSTIN (POSTN). The top downregulated microRNA in both sets was miR-219, which is predicted to bind to POSTN. Kaplan Meier analysis demonstrated that above median expression of POSTN resulted in significantly decreased survival and shorter time to disease progression (P<0.001). High POSTN and low miR-219 expression were significantly associated with the mesenchymal GBM subtype (P<0.0001).
Here, we propose a novel diagnostic method to screen for molecular cancer subtypes and genomic correlates of cellular invasion. Our findings also have potential therapeutic significance since successful molecular inhibition of invasion will improve therapy and patient survival in GBM.
尽管最近发现了新的分子靶点和途径，但仍在寻找胶质母细胞瘤（GBM）的有效治疗方法。一个新兴的领域，放射基因组学，将基因表达谱与 MRI 表型联系起来。MRI-FLAIR 是一种非侵入性诊断方式，先前发现与 GBM 中的细胞侵袭相关。因此，我们的放射基因组筛选有可能揭示侵袭的新分子决定因素。在这里，我们使用定量 MRI 体积测量和 GBM 的大规模基因和 microRNA 表达谱进行了首次全面的放射基因组分析。
基于癌症基因组图谱（TCGA），创建了具有基因、microRNA 和定量 MR 成像数据的发现和验证集。从这两个集合中，与高 FLAIR 体积相关的 top 一致基因和 microRNA 进一步通过 Kaplan-Meier 生存统计、microRNA-基因相关性分析和 GBM 分子亚型特异性分布进行了表征。
在发现（4 倍）和验证（11 倍）组中上调最多的基因是 PERIOSTIN（POSTN）。在两个集合中下调最多的 microRNA 是 miR-219，其预测与 POSTN 结合。Kaplan-Meier 分析表明，POSTN 的中位以上表达导致生存显著降低和疾病进展时间缩短（P<0.001）。POSTN 高表达和 miR-219 低表达与间充质 GBM 亚型显著相关（P<0.0001）。
在这里，我们提出了一种新的诊断方法，用于筛选分子癌症亚型和细胞侵袭的基因组相关性。我们的发现也具有潜在的治疗意义，因为成功的侵袭分子抑制将改善 GBM 的治疗和患者生存。
