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Published in: Journal of Cancer Research and Clinical Oncology 9/2010

01-09-2010 | Original Paper

Association of the GNB3 825T-allele with better survival in patients with glioblastoma multiforme

Authors: Nicolai El Hindy, Michael Adamzik, Nicole Lambertz, Hagen S. Bachmann, Karl Worm, Rupert Egensperger, Ulrich H. Frey, Siamak Asgari, Ulrich Sure, Winfried Siffert, I. Erol Sandalcioglu

Published in: Journal of Cancer Research and Clinical Oncology | Issue 9/2010

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Abstract

Purpose

Genotypes of the C825T polymorphism of the GNB3 gene encoding the G protein β3 subunit were recently associated with the prognosis of different malignomas. We investigated potential associations of GNB3 genotypes with survival of patients with glioblastoma multiforme (GBM).

Methods

One hundred and sixty-one patients suffering from GBM were retrospectively investigated. Inclusion criteria were availability of DNA and a follow-up of at least 24 months. The results were evaluated with respect to the basic clinical data, type of surgical intervention, MGMT promoter methylation, adjuvant therapy, and survival.

Results

After 2 years of first diagnosis, 128 (79.5%) of the 161 patients had died, 33 (20.5%) were alive. Kaplan–Meier curves revealed a significant higher rate of survival for homo- and heterozygous T-allele carriers (P = 0.019) with 38.5 and 25.3%, respectively, but only 11.6% for homozygous C-allele carriers. Multivariable Cox regression identified the heterozygous (hazard ratio 3.3, 95% CI 1.3–8.0, P = 0.010), as well as homozygous GNB3 825 C-allele (hazard ratio 3.7, 95% CI 1.5–9.1, P = 0.004) as an independent negative prognostic factor for 2-year survival according to the GNB3 825 TT genotype reference group.

Conclusions

Our data suggest an association of the GNB3 825TT genotype and better survival in patients with GBM.
Literature
go back to reference Burger PC, Green SB (1987) Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer 59:1617–1625CrossRefPubMed Burger PC, Green SB (1987) Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer 59:1617–1625CrossRefPubMed
go back to reference Clar H, Langsenlehner U, Krippl P, Renner W, Leithner A, Gruber G, Hofmann G, Yazdani-Biuki B, Langsenlehner T, Windhager R (2008) A polymorphism in the G protein beta3-subunit gene is associated with bone metastasis risk in breast cancer patients. Breast Cancer Res Treat 111:449–452CrossRefPubMed Clar H, Langsenlehner U, Krippl P, Renner W, Leithner A, Gruber G, Hofmann G, Yazdani-Biuki B, Langsenlehner T, Windhager R (2008) A polymorphism in the G protein beta3-subunit gene is associated with bone metastasis risk in breast cancer patients. Breast Cancer Res Treat 111:449–452CrossRefPubMed
go back to reference Demuth T, Berens ME (2004) Molecular mechanisms of glioma cell migration and invasion. J Neurooncol 70:217–228CrossRefPubMed Demuth T, Berens ME (2004) Molecular mechanisms of glioma cell migration and invasion. J Neurooncol 70:217–228CrossRefPubMed
go back to reference Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, Wong H, Liloglou T, Haylock B, Walker C (2009) Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124–131CrossRefPubMed Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, Wong H, Liloglou T, Haylock B, Walker C (2009) Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124–131CrossRefPubMed
go back to reference Eisenhardt A, Siffert W, Rosskopf D, Musch M, Mosters M, Roggenbuck U, Jockel KH, Rubben H, Lummen G (2005) Association study of the G protein beta3 subunit C825T polymorphism with disease progression in patients with bladder cancer. World J Urol 23:279–286CrossRefPubMed Eisenhardt A, Siffert W, Rosskopf D, Musch M, Mosters M, Roggenbuck U, Jockel KH, Rubben H, Lummen G (2005) Association study of the G protein beta3 subunit C825T polymorphism with disease progression in patients with bladder cancer. World J Urol 23:279–286CrossRefPubMed
go back to reference Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMed Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMed
go back to reference Hennig IM, Laissue JA, Horisberger U, Reubi JC (1995) Substance-P receptors in human primary neoplasms: tumoral and vascular localization. Int J Cancer 61:786–792CrossRefPubMed Hennig IM, Laissue JA, Horisberger U, Reubi JC (1995) Substance-P receptors in human primary neoplasms: tumoral and vascular localization. Int J Cancer 61:786–792CrossRefPubMed
go back to reference Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225 discussion 226-9PubMed Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225 discussion 226-9PubMed
go back to reference Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G, Weller M, Schackert G (2007) Long-term survival with glioblastoma multiforme. Brain 130:2596–2606CrossRefPubMed Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G, Weller M, Schackert G (2007) Long-term survival with glioblastoma multiforme. Brain 130:2596–2606CrossRefPubMed
go back to reference Lehnerdt GF, Franz P, Bankfalvi A, Grehl S, Jahnke K, Lang S, Schmid KW, Siffert W, Frey UH (2008) Association study of the G protein beta3 subunit C825T polymorphism with disease progression an overall survival in patients with head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 17:3203–3207CrossRefPubMed Lehnerdt GF, Franz P, Bankfalvi A, Grehl S, Jahnke K, Lang S, Schmid KW, Siffert W, Frey UH (2008) Association study of the G protein beta3 subunit C825T polymorphism with disease progression an overall survival in patients with head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 17:3203–3207CrossRefPubMed
go back to reference Mollemann M, Wolter M, Felsberg J, Collins VP, Reifenberger G (2005) Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer 113:379–385CrossRefPubMed Mollemann M, Wolter M, Felsberg J, Collins VP, Reifenberger G (2005) Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer 113:379–385CrossRefPubMed
go back to reference Ohgaki H, Kleihues P (2005b) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489PubMed Ohgaki H, Kleihues P (2005b) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489PubMed
go back to reference Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899CrossRefPubMed Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899CrossRefPubMed
go back to reference Rosskopf D, Manthey I, Habich C, Kielbik M, Eisenhardt A, Nikula C, Urban M, Kohnen S, Graf E, Ravens U, Siffert W (2003) Identification and characterization of G beta 3s2, a novel splice variant of the G protein beta 3 subunit. Biochem J 371:223–232CrossRefPubMed Rosskopf D, Manthey I, Habich C, Kielbik M, Eisenhardt A, Nikula C, Urban M, Kohnen S, Graf E, Ravens U, Siffert W (2003) Identification and characterization of G beta 3s2, a novel splice variant of the G protein beta 3 subunit. Biochem J 371:223–232CrossRefPubMed
go back to reference Salazar OM, Rubin P, Feldstein ML, Pizzutiello R (1979) High dose radiation therapy in the treatment of malignant gliomas: final report. Int J Radiat Oncol Biol Phys 5:1733–1740PubMed Salazar OM, Rubin P, Feldstein ML, Pizzutiello R (1979) High dose radiation therapy in the treatment of malignant gliomas: final report. Int J Radiat Oncol Biol Phys 5:1733–1740PubMed
go back to reference Schaich M, Kestel L, Pfirrmann M, Robel K, Illmer T, Kramer M, Dill C, Ehninger G, Schackert G, Krex D (2009) A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol 20:175–181CrossRefPubMed Schaich M, Kestel L, Pfirrmann M, Robel K, Illmer T, Kramer M, Dill C, Ehninger G, Schackert G, Krex D (2009) A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol 20:175–181CrossRefPubMed
go back to reference Sheu SY, Gorges R, Ensinger C, Ofner D, Farid NR, Siffert W, Schmid KW (2005) Different genotype distribution of the GNB3 C825T polymorphism of the G protein beta3 subunit in adenomas and differentiated thyroid carcinomas of follicular cell origin. J Pathol 207:430–435CrossRefPubMed Sheu SY, Gorges R, Ensinger C, Ofner D, Farid NR, Siffert W, Schmid KW (2005) Different genotype distribution of the GNB3 C825T polymorphism of the G protein beta3 subunit in adenomas and differentiated thyroid carcinomas of follicular cell origin. J Pathol 207:430–435CrossRefPubMed
go back to reference Sheu SY, Handke S, Brocker-Preuss M, Gorges R, Frey UH, Ensinger C, Ofner D, Farid NR, Siffert W, Schmid KW (2007) The C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. J Pathol 211:60–66CrossRefPubMed Sheu SY, Handke S, Brocker-Preuss M, Gorges R, Frey UH, Ensinger C, Ofner D, Farid NR, Siffert W, Schmid KW (2007) The C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. J Pathol 211:60–66CrossRefPubMed
go back to reference Siffert W (1996a) G proteins, hypertension, and coronary heart disease–novel findings and hypotheses. Kidney Blood Press Res 19:71–80CrossRefPubMed Siffert W (1996a) G proteins, hypertension, and coronary heart disease–novel findings and hypotheses. Kidney Blood Press Res 19:71–80CrossRefPubMed
go back to reference Siffert W (1996b) Genetically fixed enhanced G protein activation in essential hypertension. Kidney Blood Press Res 19:172–173CrossRefPubMed Siffert W (1996b) Genetically fixed enhanced G protein activation in essential hypertension. Kidney Blood Press Res 19:172–173CrossRefPubMed
go back to reference Siffert W (2003) Effects of the G protein beta 3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on “A splice variant of the G protein beta 3-subunit implicated in disease states does not modulate ion channels”. Physiol Genomics 13:81–84PubMed Siffert W (2003) Effects of the G protein beta 3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on “A splice variant of the G protein beta 3-subunit implicated in disease states does not modulate ion channels”. Physiol Genomics 13:81–84PubMed
go back to reference Siffert W, Forster P, Jockel KH, Mvere DA, Brinkmann B, Naber C, Crookes R, Du PHA, Epplen JT, Fridey J, Freedman BI, Muller N, Stolke D, Sharma AM, Al Moutaery K, Grosse-Wilde H, Buerbaum B, Ehrlich T, Ahmad HR, Horsthemke B, Du Toit ED, Tiilikainen A, Ge J, Wang Y, Rosskopf D et al (1999) Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. J Am Soc Nephrol 10:1921–1930PubMed Siffert W, Forster P, Jockel KH, Mvere DA, Brinkmann B, Naber C, Crookes R, Du PHA, Epplen JT, Fridey J, Freedman BI, Muller N, Stolke D, Sharma AM, Al Moutaery K, Grosse-Wilde H, Buerbaum B, Ehrlich T, Ahmad HR, Horsthemke B, Du Toit ED, Tiilikainen A, Ge J, Wang Y, Rosskopf D et al (1999) Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. J Am Soc Nephrol 10:1921–1930PubMed
go back to reference Siffert W, Rosskopf D, Erbel R (2000) Genetic polymorphism of the G protein beta3 subunit, obesity and essential hypertension. Herz 25:26–33CrossRefPubMed Siffert W, Rosskopf D, Erbel R (2000) Genetic polymorphism of the G protein beta3 subunit, obesity and essential hypertension. Herz 25:26–33CrossRefPubMed
go back to reference Simpson JR, Horton J, Scott C, Curran WJ, Rubin P, Fischbach J, Isaacson S, Rotman M, Asbell SO, Nelson JS et al (1993) Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials. Int J Radiat Oncol Biol Phys 26:239–244PubMed Simpson JR, Horton J, Scott C, Curran WJ, Rubin P, Fischbach J, Isaacson S, Rotman M, Asbell SO, Nelson JS et al (1993) Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials. Int J Radiat Oncol Biol Phys 26:239–244PubMed
go back to reference Singh SK, Clarke ID, Hide T, Dirks PB (2004) Cancer stem cells in nervous system tumors. Oncogene 23:7267–7273CrossRefPubMed Singh SK, Clarke ID, Hide T, Dirks PB (2004) Cancer stem cells in nervous system tumors. Oncogene 23:7267–7273CrossRefPubMed
go back to reference Smith JS, Jenkins RB (2000) Genetic alterations in adult diffuse glioma: occurrence, significance, and prognostic implications. Front Biosci 5:D213–D231CrossRefPubMed Smith JS, Jenkins RB (2000) Genetic alterations in adult diffuse glioma: occurrence, significance, and prognostic implications. Front Biosci 5:D213–D231CrossRefPubMed
go back to reference Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018CrossRefPubMed Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018CrossRefPubMed
go back to reference Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401CrossRefPubMed Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401CrossRefPubMed
go back to reference Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed
go back to reference Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466CrossRefPubMed Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466CrossRefPubMed
go back to reference Yamaguchi K, Kugimiya T, Miyazaki T (2005a) Substance P receptor in U373 MG human astrocytoma cells activates mitogen-activated protein kinases ERK1/2 through Src. Brain Tumor Pathol 22:1–8CrossRefPubMed Yamaguchi K, Kugimiya T, Miyazaki T (2005a) Substance P receptor in U373 MG human astrocytoma cells activates mitogen-activated protein kinases ERK1/2 through Src. Brain Tumor Pathol 22:1–8CrossRefPubMed
go back to reference Yamaguchi K, Richardson MD, Bigner DD, Kwatra MM (2005b) Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta. Cancer Chemother Pharmacol 56:585–593CrossRefPubMed Yamaguchi K, Richardson MD, Bigner DD, Kwatra MM (2005b) Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta. Cancer Chemother Pharmacol 56:585–593CrossRefPubMed
go back to reference Yao XH, Ping YF, Chen JH, Chen DL, Xu CP, Zheng J, Wang JM, Bian XW (2008a) Production of angiogenic factors by human glioblastoma cells following activation of the G protein coupled formylpeptide receptor FPR. J Neurooncol 86:47–53CrossRefPubMed Yao XH, Ping YF, Chen JH, Chen DL, Xu CP, Zheng J, Wang JM, Bian XW (2008a) Production of angiogenic factors by human glioblastoma cells following activation of the G protein coupled formylpeptide receptor FPR. J Neurooncol 86:47–53CrossRefPubMed
go back to reference Yao XH, Ping YF, Chen JH, Xu CP, Chen DL, Zhang R, Wang JM, Bian XW (2008b) Glioblastoma stem cells produce vascular endothelial growth factor by activation of a G protein coupled formylpeptide receptor FPR. J Pathol 215:369–376CrossRefPubMed Yao XH, Ping YF, Chen JH, Xu CP, Chen DL, Zhang R, Wang JM, Bian XW (2008b) Glioblastoma stem cells produce vascular endothelial growth factor by activation of a G protein coupled formylpeptide receptor FPR. J Pathol 215:369–376CrossRefPubMed
go back to reference Zhou Y, Bian X, Le Y, Gong W, Hu J, Zhang X, Wang L, Iribarren P, Salcedo R, Howard OM, Farrar W, Wang JM (2005) Formylpeptide receptor FPR and the rapid growth of malignant human gliomas. J Natl Cancer Inst 97:823–835CrossRefPubMed Zhou Y, Bian X, Le Y, Gong W, Hu J, Zhang X, Wang L, Iribarren P, Salcedo R, Howard OM, Farrar W, Wang JM (2005) Formylpeptide receptor FPR and the rapid growth of malignant human gliomas. J Natl Cancer Inst 97:823–835CrossRefPubMed
Metadata
Title
Association of the GNB3 825T-allele with better survival in patients with glioblastoma multiforme
Authors
Nicolai El Hindy
Michael Adamzik
Nicole Lambertz
Hagen S. Bachmann
Karl Worm
Rupert Egensperger
Ulrich H. Frey
Siamak Asgari
Ulrich Sure
Winfried Siffert
I. Erol Sandalcioglu
Publication date
01-09-2010
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 9/2010
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-010-0797-8

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