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Comparative Study
. 2015 Oct 13;6(31):31844-56.
doi: 10.18632/oncotarget.5571.

Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Adam M Fontebasso  1 , Margret Shirinian  2 , Dong-Anh Khuong-Quang  3 , Denise Bechet  3 , Tenzin Gayden  3 , Marcel Kool  3 , Nicolas De Jay  3 , Karine Jacob  3 , Noha Gerges  3 , Barbara Hutter  4 , Huriye Şeker-Cin  5 , Hendrik Witt  5   6 , Alexandre Montpetit  7 , Sébastien Brunet  7 , Pierre Lepage  7 , Geneviève Bourret  7 , Almos Klekner  8 , László Bognár  8 , Peter Hauser  9 , Miklós Garami  9 , Jean-Pierre Farmer  10 , Jose-Luis Montes  10 , Jeffrey Atkinson  10 , Sally Lambert  11 , Tony Kwan  7 , Andrey Korshunov  12 , Uri Tabori  13 , V Peter Collins  11 , Steffen Albrecht  14 , Damien Faury  3 , Stefan M Pfister  5   6 , Werner Paulus  15 , Martin Hasselblatt  15 , David T W Jones  5 , Nada Jabado  1   3
Affiliations
Comparative Study

Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Adam M Fontebasso et al. Oncotarget. .

Abstract

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

Keywords: BRAF; MDM2; PLK2; aneuploidy; pilocytic astrocytoma.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Characterization of aneuploidy observed in pilocytic astrocytoma
a., Gains in 50 aneuploid PA samples (upper panel), frequency of specific gains, and significance (P < 0.05; Fisher's Exact Test; lower panel). b., Neuroanatomical distribution of aneuploid PA tumors favors non-cerebellar areas. c., Increased aneuploidy observed amongst adult PA tumors (P = 0.0002; Fisher's Exact Test). d., Age of patients with aneuploid and euploid PA tumors (P < 0.0076; unpaired two-tailed t-test).
Figure 2
Figure 2. Aneuploidy is differentially associated with prominent MAPK alterations in PA with a strong effect on global gene expression
a., Frequency of aneuploidy within BRAF fusion (P = 0.0076; Fisher's Exact Test) a. and BRAF mutation (P = 0.0074; Fisher's Exact Test) b. subsets of PA tumors. c., Strong effect of aneuploidy on global gene expression in PA at FDR < 0.001.
Figure 3
Figure 3. Comparative gene expression analysis identifies specific pathways aberrantly regulated in aneuploid tumors
a., Aneuploidy signatures demonstrate enrichment of CNS development, cell cycle and unfolded protein binding pathways. b., Chromosomal mapping of the 558 genes demonstrates enrichment within chromosomes involved in aneuploid gains. c., d., Over-expression of candidates MDM2 c. and PLK2 (d) within the aneuploid PA subgroup (P = 1.5×10−3 and FDR adjusted P-value = 3.74×10−8 respectively; ANOVA). e., Correlation of MDM2 and PLK2 expression in 122 PAs with available aneuploid data (P = 0.01).
Figure 4
Figure 4. MDM2 expression analysis of CNS tumors and tissues reveals high expression in aneuploid PA
a., MDM2 expression is highest in aneuploid PA tumors (P = 4.0×10−109, ANOVA). NB = normal brain, CB = normal cerebellum, GBM = glioblastoma, DIPG = diffuse intrinsic pontine glioma, pHGG = pediatric high-grade glioma, EP = ependymoma, PA = pilocytic astrocytoma. b., c., d., MDM2 over-expression in adult patients (>18 years) (P = 1.1×10−4) b., BRAF fusion negative (P = 8.0×10−6) c. and BRAF mutant PA (P = 9.3×10−7) d.. P-values calculated using ANOVA.
Figure 5
Figure 5. Pathway convergence leading to aneuploidy in PA
See this image and copyright information in PMC

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