Abstract
Cancer biomarkers with a strong predictive power for diagnosis/prognosis and a potential to be therapeutic targets have not yet been fully established. Here we employed a loss-of-function screen in glioblastoma (GBM), an infiltrative brain tumor with a dismal prognosis, and identified 20 survival kinase genes (SKGs). Survival analyses using The Cancer Genome Atlas (TCGA) datasets revealed that the expression of CDCP1, CDKL5, CSNK1E, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 stratified GBM prognosis with or without temozolomide (TMZ) treatment as a covariate. For the first time, we found that GBM patients with a high level of NEK9 and PIK3CB had a greater chance of having recurrent tumors. The expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary GBM tumors was associated with recurrence-related prognosis. Notably, the level of PIK3CB in recurrent tumors was much higher than that in newly diagnosed ones. Congruent with these results, genes in the PI3K/AKT pathway showed a significantly strong correlation with recurrence rate, further highlighting the pivotal role of PIK3CB in the disease progression. Importantly, 17 SKGs together presented a novel GBM prognostic signature. SKGs identified herein are associated with recurrence rate and present prognostic significance in GBM, thereby becoming attractive therapeutic targets.
Highlights
Glioblastoma (GBM) is the most common and deadly subtype of malignant brain tumors [1]
We divided the human U87MG GBM cells transduced with viruses harboring the above library of short hairpin RNAs (shRNAs) into two parts: one part was collected immediately as passage 0 (P0); the other part continued a 7-day culture and was saved as passage 7 (P7)
We found that 63 shRNAs had 2-fold less of the sequencing read number at P7 compared to P0 (Figure 1B)
Summary
Glioblastoma (GBM) is the most common and deadly subtype of malignant brain tumors [1]. The median survival of GBM patients receiving aforementioned concurrent therapies is only 14.6 months [4] These grim facts demonstrate an urgent need of new and effective treatments as well as powerful prognostic markers to assist these treatments for this deadly disease. MGMT methylation was confirmed as an important prognosis marker associated with improved OS of newly diagnosed GBM patients receiving TMZ [6,7,8,9,10,11,12]. An inhibitor of IDH1 significantly retards GBM growth through inducing differentiation [22] This genetic approach often lacks functional information of candidate genes thereby requiring a further extensive and time-consuming investigation
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