Expression Levels of RAD51 Inversely Correlate with Survival of Glioblastoma Patients.

Christopher Morrison,Abhay Sanan,Eric Weterings,Martin Weinand,Daruka Mahadevan,Baldassarre Stea

doi:10.3390/cancers13215358

Abstract

Simple SummaryIdentifying prognostic and predictive biomarkers for glioblastoma (GBM), a primary brain tumor, is essential in improving patient survival. We utilized gene expression profiling to investigate a uniform population of GBM patients who had been treated with surgery and adjuvant radiation therapy versus normal brain tissue, and identified high RAD51 expression as a poor prognostic marker that is amenable to therapeutic intervention. This observation was confirmed utilizing a publicly available gene expression dataset in a cohort of GBM patients.Treatment failures of glioblastoma (GBM) occur within high-dose radiation fields. We hypothesized that this is due to increased capacity for DNA damage repair in GBM. We identified 24 adult GBM patients treated with maximal safe resection followed by radiation with concurrent and adjuvant temozolomide. The mRNA from patients was quantified using NanoString Technologies’ nCounter platform and compared with 12 non-neoplastic temporal lobe tissue samples as a control. Differential expression analysis identified seven DNA repair genes significantly upregulated in GBM tissues relative to controls (>4-fold difference, adjusted p values < 0.001). Among these seven genes, Cox proportional hazards models identified RAD51 to be associated with an increased risk of death (HR = 3.49; p = 0.03). Kaplan–Meier (KM) analysis showed that patients with high RAD51 expression had significantly shorter OS compared to low levels (median OS of 10.6 mo. vs 20.1 mo.; log-rank p = 0.03). Our findings were validated in a larger external dataset of 162 patients using publicly available gene expression data quantified by the same NanoString technology (median OS of 13.8 mo. vs. 17.4 mo; log-rank p = 0.006). Within this uniformly treated GBM population, RAD51, in the homologous recombination pathway, was overexpressed (vs. normal brain) and inversely correlated with OS. High RAD51 expression may be a prognostic biomarker and a therapeutic target in GBM.

Highlights

Damage repair in a patient population with glioblastoma, we identified several genes from this is the first study to demonstrate an increase in DNA repair gene expression over the homologous recombination (HR)
The findings reported here have therapeutic implications; if the prognostic role of RAD51 is confirmed by a prospective study, adaptive management strategies could be designed based on the level of RAD51 expression, such as clinical trials of different radiation regimens and/or intensity; for example, patients with high repair capacity could be assigned to receive hypo-fractionated radiation therapy to compensate for the increased cellular capacity to repair DNA double-strand breaks [36,37]
More importantly, the results reported here point the way toward a potential therapeutic target that could be exploited to increase the sensitivity of GBM to radiation, a concept that already has support in in vitro studies of inhibition of the c-MET receptor tyrosine kinase, which in turn leads to a decrease in Rad51 expression levels, thereby increasing the radio-sensitivity of GBM cell lines [35]

Summary

Introduction

The current standard of care, which consists of maximal safe resection followed by 60 Gy of fractionated radiation with concurrent and adjuvant temozolomide (TMZ) for 6 months, was established more than 15 years ago by the Stupp’s NCIC/EORTC trial [2]. This treatment approach is rarely curative, though it does extend the median overall survival (OS) of patients with glioblastoma by about 2 months, to a total of approximately 14 months [2]. New treatment approaches are needed in order to change the prognosis for this mostly incurable disease

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