Characterization of Long-Surviving Glioblastomas by High Resolution Array Comparative Genomic Hybridization (aCGH)
S Sharma, A Free, Y Mei, SC Peiper, Z Wang. Medical College of Georgia, Augusta, GA
Background: Glioblastoma is the most common primary brain tumor with a median survival of about 12 months, despite multimodal treatment. Nevertheless, a small fraction of glioblastoma patients have long-term survival; very little genomic data is available to explain this long survival. Aiming to identify genes critical to evolution of this favorable subset, we performed high resolution aCGH in long-surviving glioblastomas.
Design: Following receipt of Human Assurance Committee approval, three cases of long surviving glioblastomas (over 24 months) with age range 55 to 62 years were identified at our institution. Two of these were histologically usual glioblastoma, and one a gliosarcoma variant. Paired biopsies at initial diagnosis and recurrence (24 months) were examined in one case. Two others had only one biopsy with optimal tissue for analysis (one at initial diagnosis and other at recurrence). Representative sections from formalin-fixed, paraffin-embedded (FFPE) tumor tissues showing optimal histology were utilized for DNA extraction using the TrimGen Wax Free kit and analyzed for DNA copy number changes using Affymetrix SNP250K chips.
Results: DNA from archival FFPE tissues yielded adequate coverage, as assessed by analysis of SNPs. Initial biopsies had no chromosomal or subchromosomal gains or losses. The case with paired samples illustrated that recurrent tumor had accumulation of significant chromosomal losses and gains, with limited overlap (chromosome 10). One case had amplification of EGFR gene in initial specimen. The gliosarcoma had amplification of WNT5B. There were no detectable abnormalities in the P53 pathway. Abnormalities in the PI3K pathway were limited to PTEN loss. One patient had a hemizygous deletion of PTEN at initial diagnosis and its loss of heterozygosity in the recurrence, which also had deletion of P16. There were no other abnormalities of genes in the RB1 pathway. All three cases had a deletion in chromosome 20q of approximately 140kb that contained 4 genes (one with a family member expressed in neurons and mutated in Charcoat-Marie-Tooth disease).
Conclusions: Glioblastomas with prolonged survival present with limited abnormalities in gene copy number. Relatively few copy number changes involved families of genes known to play key role in regulation of tumor growth. Array CGH analysis of GBM should provide informative molecular karyotypes. Larger future studies with unbiased, genome-wide profiling carry the potential to identify genomic insight into clinical subgroups of GBM.
Category: Special Category for 2009 - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 247, Tuesday Morning