Abstract
There is limited knowledge on the in vivo behavior of amplified regions in human tumors. First evidence indicates that amplicon structures are largely maintained in recurrent tumors. Here, we investigated the fate of amplified regions in several independent cases of recurrent glioblastoma and the possible association of 12q13–21 amplifications and survival. We analyzed 12q13–21 amplicon numbers and sizes in glioblastoma and their recurrences by array-CGH. The majority of the 12q13–21 amplicons found in the original tumor are lost in the subsequent recurrence. Likewise, the majority of the amplicons found in the first recurrence are lost in the second recurrence. The remaining amplicons of recurrences often expanded or were maintained in size. Because of re-emergences and de novo appearances of amplicons, however, the overall number of amplicons did not decrease in the recurrences. Understanding genetic changes including gene amplifications in the development of tumor recurrences will contribute to rational therapeutic strategies for an improved patient survival. We recognized a significant longer survival time in glioblastoma patients that lack amplifications of either CDK4, CYP27B1, XRCC6BP1 (KUB3), or MDM2.
Gene amplifications that are commonly found in human tumors result from a highly complex process that is largely still an enigma. Previous concepts suggest the de novo generation of extended DNA amplicons that are subsequently shortened to leave primarily genes amplified that contribute to tumor progression.1, 2 Other studies suggest that amplicons of different sizes are present at the beginning of the amplification process, and amplicons of smaller sizes are preferentially amplified in the further development of amplification units.3 Both hypotheses are mainly based on the analysis of drug-resistant cells. There is rather limited knowledge on the in vivo behavior of amplified regions in the tumor. Comparative analyses of gene amplifications both in the original tumors and their recurrences allow tracking the fate of an amplicon in vivo. Recently, an invariable co-amplification pattern of the MYCN amplicon in neuroblastoma showed an amplicon structure that was largely maintained in subsequent biopsies.4 Analysis of EGFR and KIT amplifications in human glioma also indicated that gene amplification persists in recurrent tumors.5, 6 We have shown that an extended amplified region on chromosome 12q15–21 was maintained in 4 recurrences of a glioblastoma over 6 years.7 Here, we investigated the in vivo behavior of amplified regions in several independent cases of recurrent glioblastoma and the impact of 12q13–21 amplifications on survival.
CGH: comparative genomic hybridization; GBM: glioblastoma; KPS: Karnofsky performance status; TMZ: temozolomide; WHO: world health organization