Different molecular patterns in glioblastoma multiforme subtypes upon recurrence

Abstract

One of the hallmarks of glioblastoma is its inherent tendency to recur. At this point patients with relapsed GBM show a survival time of only few months. The molecular basis of the recurrence process in GBM is still poorly understood. The aim of the present study was to investigate the genetic profile of relapsed GBM compared to their respective primary tumors. We have included 20 paired GBMs. In all tumor samples, we have analyzed p53 and PTEN status by sequencing analysis, EGFR amplification by semiquantitative PCR and a wide-genome fingerprinting was performed by microsatellite analysis. Among primary GBM, we observed twelve type 2 GBM, four type 1 GBM and four further GBM showing neither p53 mutations nor EGFR amplification (non-type 1-non-type 2 GBM). Upon recurrence, we have detected two molecular patterns of tumor progression: GBM initially showing either type 1 or type 2 profiles conserved them at the time of relapse. In contrast, non-type 1-non-type 2 GBM acquired the typical pattern of type 2 GBM and harbor EGFR amplification without p53 mutation. New PTEN mutations upon relapse were only detected in type 2 GBM. Additional LOH were more frequently identified in relapses of type 2 GBM than in those showing the type 1 signature. Taken together, our results strongly suggest that recurrences of GBM may display two distinct pattern of accumulation of molecular alterations depending on the profile of the original tumor.

Fig. 1

Upper row: wild type sequence of p53. Lower row: base exchange mutation (GGA→GTA) of p53 (exon 8, codon 266), predicting the aminoacid substitution Gly→Val. The arrow indicates the base exchange

Fig. 2

Upper row: wild type sequence of PTEN. Lower row: base exchange mutation (CAT→AAT) of PTEN (exon 4, codon 75) predicting the aminoacid substitution His→Asn. The arrow indicates the base exchange

Fig. 3

Graphic showing two molecular patterns of GBM recurrence