title: The CDKN2A G500 allele is more frequent in GBM patients with no defined telomere maintenance mechanism tumors and is associated with poorer survival.
abstract: Prognostic markers for glioblastoma multiforme (GBM) are important for patient management. Recent advances have identified prognostic markers for GBMs that use telomerase or the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance. Approximately 40% of GBMs have no defined telomere maintenance mechanism (NDTMM), with a mixed survival for affected individuals. This study examined genetic variants in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene that encodes the p16(INK4a) and p14(ARF) tumor suppressors, and the isocitrate dehydrogenase 1 (IDH1) gene as potential markers of survival for 40 individuals with NDTMM GBMs (telomerase negative and ALT negative by standard assays), 50 individuals with telomerase, and 17 individuals with ALT positive tumors. The analysis of CDKN2A showed NDTMM GBMs had an increased minor allele frequency for the C500G (rs11515) polymorphism compared to those with telomerase and ALT positive GBMs (p = 0.002). Patients with the G500 allele had reduced survival that was independent of age, extent of surgery, and treatment. In the NDTMM group G500 allele carriers had increased loss of CDKN2A gene dosage compared to C500 homozygotes. An analysis of IDH1 mutations showed the R132H mutation was associated with ALT positive tumors, and was largely absent in NDTMM and telomerase positive tumors. In the ALT positive tumors cohort, IDH1 mutations were associated with a younger age for the affected individual. In conclusion, the G500 CDKN2A allele was associated with NDTMM GBMs from older individuals with poorer survival. Mutations in IDH1 were not associated with NDTMM GBMs, and instead were a marker for ALT positive tumors in younger individuals.
authors: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors: Janice A
authors: JA
authors: Royds
authors: Shafagh
authors: S
authors: Al Nadaf
authors: Anna K
authors: AK
authors: Wiles
authors: Yu-Jen
authors: YJ
authors: Chen
authors: Antonio
authors: A
authors: Ahn
authors: Alisha
authors: A
authors: Shaw
authors: Sara
authors: S
authors: Bowie
authors: Frederic
authors: F
authors: Lam
authors: Bruce C
authors: BC
authors: Baguley
authors: Antony W
authors: AW
authors: Braithwaite
authors: Martin R
authors: MR
authors: MacFarlane
authors: Noelyn A
authors: NA
authors: Hung
authors: Tania L
authors: TL
authors: Slatter
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D019098:Telomerase; D016615:Telomere
chemical_list: D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D019098:Telomerase