YKL-40 Expression is Associated with Poorer Response to Radiation and Shorter Overall Survival in Glioblastoma

Abstract

Purpose: YKL-40 is a secreted protein that has been reported to be overexpressed in epithelial cancers and gliomas, although its function is unknown. Previous data in a smaller sample set suggested that YKL-40 was a marker associated with a poorer clinical outcome and a genetically defined subgroup of glioblastoma. Here we test these findings in a larger series of patients with glioblastoma, and in particular, determine if tumor YKL-40 expression is associated with radiation response. Experimental Design: Patients (n = 147) with subtotal resections were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. An additional set (n = 140) of glioblastoma patients who underwent a gross-total resection was tested to validate the survival association and extend them to patients with minimal residual disease. Results: In the subtotal resection group, higher YKL-40 expression was significantly associated with poorer radiation response, shorter time to progression and shorter overall survival. The association of higher YKL-40 expression with poorer survival was validated in the gross-total resection group. In multivariate analysis with both groups combined (n = 287), YKL-40 was an independent predictor of survival after adjusting for patient age, performance status, and extent of resection. YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization. YKL-40 was significantly associated with 10q loss. Conclusions: The findings implicate YKL-40 as an important marker of therapeutic response and genetic subtype in glioblastomas and suggest that it may play an oncogenic role in these tumors.

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

“…Immunohistochemical analysis was performed as described previously. 17 Formalin-fixed and paraffin-embedded tissue sections (2 lm) were deparaffinized stepwise in xylene and rehydrated in graded solutions of ethanol (100%, 95%, and 80%, respectively) followed by phosphatebuffered saline (PBS) and 0.1 mol/L Tris buffer (pH 8.0). Antigen retrieval was performed at 95 C for 40 minutes using 0.01 M sodium citrate buffer (pH 6.0).…”

“…Identification of staining pattern was performed using a modified 2-tiered system as previously described. 17 The most distinctive areas were picked up for this scoring system and subsequently dichotomized into total-Nurr1-high versus total-Nurr1-low or cytoplasmic-Nurr1-high versus cystoplasmic-Nurr1-low.…”

Experimental anti‐angiogenesis causes upregulation of genes associated with poor survival in glioblastoma

“…Samples, for which no threshold cycle could be determined, were excluded for that particular gene. Values of CHI3L2, IL1B, EGLN3, APOC1 and PI3 were compared with those of CHI3L1, which encodes for the poor prognosis marker YKL-40 22 using nonparametric Spearman's correlation. To determine whether expression of the selected genes differs FIGURE 1 -Biological effects of vascular endothelial growth factor (VEGF) siRNA in U87 glioma cells in vitro (a) Three different small interfering RNAs (siRNAs) targeting VEGF-A were designed.…”

Molecular genetics of oligodendrogliomas: a model for improved clinical management in the field of neurooncology

“…77,80,93,102 Furthermore, mutation of PTEN, a 10q gene, has also been correlated with poor prognosis. 28,99 Additional molecular markers predicting a negative prognosis for patients with astrocytic gliomas have included the following: loss of chromosome 9p or CDKN2A deletion, 80 gains of 7p and 7q, 57 activated phosphatidylinositol 3-kinase, 21 YKL-40, 78 and a dysfunctional RB pathway. 2 Furthermore, CGH 13,57,117 and gene expression profiling 62,87 have also provided novel sources of prognostic information.…”

“…78 Most recently, EGFR status has been investigated in astrocytic gliomas treated with erlotinib, a small-molecule inhibitor of EGFR. One study demonstrated that tumors with high levels of EGFR expression and low levels of phosphorylated PKB/Akt responded better to erlotinib than lesions with low levels of EGFR and high levels of phosphorylated PKB/Akt.…”