Decorin Expression Is Associated With Diffusion MR Phenotypes in Glioblastoma

Abstract

INTRODUCTION: Significant evidence from multiple phase II trials have suggested diffusion-weighted imaging estimates of apparent diffusion coefficient (ADC) are a predictive imaging biomarker for survival benefit for recurrent glioblastoma when treated with anti-VEGF therapies, including bevacizumab, cediranib, and cabozantinib. Despite this observation, the underlying mechanism linking anti-VEGF therapeutic efficacy with diffusion MR characteristics remains unknown. We hypothesized that a high expression of decorin, a small proteoglycan that has been associated with sequestration of pro-angiogenic signaling as well as reduction in the viscosity of the extracellular environment, may be associated with elevated ADC. METHODS: A differential gene expression analysis was carried out in human glioblastoma samples in whom preoperative diffusion imaging was obtained. ADC histogram analysis was carried out to calculate preoperative ADCL values, the average ADC in the lower distribution using a doubleGaussian mixed model. The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) databases were queried to identify diffusion imaging and levels of decorin protein expression. Patients with recurrent glioblastoma who undergo resection prospectively had targeted biopsies based on the ADC analysis collected. These samples were stained for decorin and quantified using whole-slide image analysis software. RESULTS: Differential gene expression analysis between tumors associated with high and low preoperative ADCL showed that patients with high ADCL had increased decorin gene expression. Patients from the TCGA database with elevated ADCL had a significantly higher level of decorin gene expression (P = .01). These patients had a survival advantage with a log-rank analysis (P = .002). Patients with preoperative diffusion imaging had multiple targeted intraoperative biopsies stained for decorin. Patients with high ADCL had increased decorin expression on immunohistochemistry (P = .002). CONCLUSION: Increased ADCL on diffusion MR imaging is associated with high decorin expression as well as increased survival in glioblastoma. Decorin may play an important role the imaging features on diffusion MR and anti-VEGF treatment efficacy. Decorin expression may serve as a future therapeutic target in patients with favorable diffusion MR characteristics.