Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age - PubMed (original) (raw)

Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age

Yohan Lee et al. BMC Med Genomics. 2008.

Abstract

Background: Glioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear.

Methods: We collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age.

Results: This meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype.

Conclusion: The survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients.

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Figures

Figure 1

Figure 1

Gene expression-based profiles related to survival duration across GBM tumours. A. 377 probesets were used to classify the GBMs available on the U133A and U133 Plus 2.0 arrays, while 177 probesets were used to classify the tumours available on the U95Av2 arrays. The four glioblastoma types: PN: ProNeural (yellow, n = 77), Pro: Proliferative (blue, n = 61), ProMes: Proliferative-Mesenchymal (purple n = 29), and Mes: Mesenchymal (red, n = 100). B. Percent composition of Long (LTS), Medium (MTS), and Short (STS) term survival across the three glioma gene-signature tumour types. Over one-third of PN-classified tumour patients survive over 2 years, while over half of Pro, ProMes, and Mes classified tumour patients succumb in less than 1 year.

Figure 2

Figure 2

Kaplan-Meier analysis of GBM patient survival according to predictive gene expression signatures and age alone. A. PN GBM patients vs. non-PN GBM patients. Molecularly categorized GBM patient survival comparison shows PN GBMs survive longer than non-PN GBMs (Pro, Mes, and ProMes). PN GBM patient survival (mean = 2.2 years, median = 1.4 years) vs. non-PN GBM patient survival (mean = 1.2 years, median = 0.9 years). B. GBM patient age difference for survival: younger than age 40 vs. older than age 40. GBM patients younger than age 40 survive longer than GBM patients older than age 40. GBM age < 40 patient survival (mean = 2.1 years, median = 1.3 years) vs. GBM age > 40 patient survival (mean = 1.4 years, median = 0.9 years).

Figure 3

Figure 3

Kaplan-Meier analysis of GBM patient survival for Pro, Mes, and ProMes GBM patients according to age. GBM patients suffering from Pro, Mes, and ProMes tumours do not survive any better if younger than age 40 than identically gene expression-classified GBM patients older than the age of 40.

Figure 4

Figure 4

Kaplan-Meier analysis of GBM patient survival partitioned by age and predictive expression signature. A. GBM patients younger than age 40 partitioned by PN status versus non-PN status. Younger patients with PN GBMs survive longer than fellow younger patients with non-PN GBMs. PN GBM patients age < 40 survival (mean = 3.0 years, median = 2.9 years) vs. non-PN GBM patients age < 40 survival (mean = 1.4 years, median = 0.8 years). B. GBM patients older than age 40 partitioned by PN status versus non-PN status. Older patients with PN GBMs survive longer than fellow older patients with non-PN GBMs. PN GBM patients age > 40 survival (mean = 1.9 years, median = 1.1 years) vs. non-PN GBM patients age > 40 survival (mean = 1.2 years, median = 0.9 years).

References

    1. 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, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330. - DOI - PubMed
    1. Omuro AM, Faivre S, Raymond E. Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther. 2007;6:1909–1919. doi: 10.1158/1535-7163.MCT-07-0047. - DOI - PubMed
    1. CBTRUS. 2005–2006 Statistical Report: Primary Brain Tumors in the United States Statistical Report, 1998–2002 (Years Data Collected) 2006.
    1. Louis DN, Posner J, Jacobs T, Kaplan R. Report of the Brain Tumor Progress Review Group. National Institutes of Health: Bethesda, MD; 2000.
    1. Dong S, Nutt CL, Betensky RA, Stemmer-Rachamimov AO, Denko NC, Ligon KL, Rowitch DH, Louis DN. Histology-based expression profiling yields novel prognostic markers in human glioblastoma. J Neuropathol Exp Neurol. 2005;64:948–955. doi: 10.1097/01.jnen.0000186940.14779.90. - DOI - PMC - PubMed

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