Clinical Study
Role of the GNAS1 T393C polymorphism in patients with glioblastoma multiforme

https://doi.org/10.1016/j.jocn.2011.02.044Get rights and content

Abstract

The T393C polymorphism of the GNAS1 locus, which encodes the Gαs protein, has recently been found to be associated with patient outcome in various malignancies. We investigated the association between GNAS1 genotype and survival among patients suffering from glioblastoma multiforme (GBM). One hundred and sixty-two patients with GBM were retrospectively investigated. Inclusion criteria were availability of DNA and, for surviving patients, a follow-up of at least 24 months. The results were analysed based on clinical data, type of surgical intervention, adjuvant therapy, and 2-year survival. At the 2-year follow up, 79.6% of patients had died. Two-year survival rates were as follows: CC-homozygous patients, 15.8%; CT-heterozygous patients, 23.1%; and TT-homozygous patients, 18.2% (p = 0.461). Subgroup analysis revealed different 2-year survival rates in the group that underwent stereotactic biopsy, with 0% for CC-homozygous, 2.8% for CT-heterozygous, and 15.4% survival for TT-homozygous patients, but the differences were not statistically significant (p = 0.229). Our results indicate that there is no association between the GNAS1 T393C polymorphism and 2-year survival among patients with GBM.

Introduction

Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumour, with incidences of 7.3 per 100 000 people per year in the USA[1], [2] and 5–6 per 100 000 people per year in Europe.3 GBM can be differentiated into primary and secondary GBM. The primary type is more common and arises de novo. Older patients are more prone to developing primary GBM, and the malignancy presents at diagnosis as a full-blown tumour, without clinical, radiological, or histopathological evidence of a precursor lesion.[4], [5] Secondary GBM is found in younger patients and slowly progresses from a low-grade diffuse tumour (World Health Organization grade II) or anaplastic astrocytoma (World Health Organization grade III).[4], [5], [6]

Despite modern techniques, such as intraoperative tumour visualisation, complete resection of GBM remains impossible due to its infiltrating nature.[7], [8] Therefore, the prognosis for patients remains poor and relapse is inevitable. The treatment of choice is surgical reduction, followed by radiotherapy with concomitant and adjuvant temozolomide chemotherapy. Median survival is 14.6 months.9

GBM originates sporadically, and only a few genetic factors are known to play a role.10 The most important prognostic genetic marker is MGMT (O-6-methylguanine-DNA methyltransferase)-promoter methylation status. Patients with methylation of the MGMT-promoter have a better outcome after temozolomide chemotherapy, with a median survival of 21.7 months.[11], [12] Clinical parameters that impact on prognosis in patients with GBM include young age, good Karnofsky performance status, and radical microsurgical resection.13 Nevertheless, due to diffuse invasion, microvascular proliferation, necrosis and intense anti-apoptosis, GBM seems to be resistant to all cancer therapies and remains incurable.[14], [15], [16], [17], [18]

Common proteins associated with apoptosis and survival in GBM patients are G-proteins.[10], [19], [20] Heterotrimeric G-proteins communicate signals from a large family of receptors to several distinct intracellular signalling pathways, thereby controlling a broad range of biological processes including cell growth, transcription and motility.[21], [22] The gene GNAS1 encodes the ubiquitously expressed Gαs subunit of heterotrimeric G-proteins. In vitro experiments suggest that increased expression of Gαs is associated with enhanced apoptosis and that the second messenger cyclic AMP, which functions downstream of the G-proteins, plays a major role in pro-apoptotic processes.[23], [24], [25], [26], [27] We have recently shown that the common T393C single nucleotide polymorphism (SNP) of the GNAS1 gene is significantly associated with clinical course among patients with various malignancies. Patients carrying the T-allele have prolonged survival compared with patients harbouring the C-allele. This association is possibly mediated by an increase in the apoptotic rate in patients harbouring the T-allele.[28], [29], [30], [31], [32], [33], [34], [35] To date, the impact of the GNAS1 T393C polymorphism on survival in GBM has not been investigated. Thus, the aim of the present study was to determine the influence of this polymorphism on prognosis in GBM.

Section snippets

Patients and methods

The study was conducted according to the Declaration of Helsinki and approved by the local ethics committee of the University Hospital of Essen. Informed consent was obtained from all patients.

Clinical data

Patients’ medical records were reviewed, and follow-up data were collected in cooperation with the responsible neurosurgeon and/or family physician. The data were evaluated with respect to basic demographic data, including sex, age, KPS, surgical procedure, adjuvant therapy, MGMT-promoter methylation status, and survival over the 2-year follow up period. Determination of MGMT-promoter methylation status was not performed routinely during the study period; rather, it was analysed

Discussion

Although there are multimodal and aggressive treatment options for GBM, survival remains poor, ranging from 12 to 14.6 months.[8], [9] Much effort has been expended in attempts to identify predictive markers for survival in GBM; however, to date, only MGMT-promoter methylation status has been established as a valuable marker.11 Patients with methylation at the MGMT-promoter have better outcomes after temozolomide chemotherapy, with a median survival of 21.7 months. There seems to be a subgroup of

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