gms | German Medical Science

Objective: Although medulloblastoma is capable of differentiation along astrocytic lines, this entity has been rarely observed in metachronous association with astrocytomas. We have performed extensive genetic and epigenetic investigation of 26 medulloblastomas, 10 glioblastomas (GBM) and normal tissue. Furthermore, we have contrasted these validated signatures with the molecular profiles of one metachronous GBM occurring as a local relapse of a medulloblastoma after surgical resection and radiotherapy.

Method: Tumor specimens were assessed by histological, immunohistochemical and molecular analyses. Amplification of EGFR, deletions of PTEN and inactivation of TP53 were investigated. Tumor instability was assessed by DNA mismatch repair analysis. In order to define major epigenetic signatures we have used a DNA methylation platform to quantify the DNA methylation level of 1,505 CpG dinucleotides (807 genes). Bisulfite sequencing was performed to confirm array results.

Results: By immunohistochemistry, medulloblastomas and GBM differed in GFAP and synaptophysin expression. EGFR was only amplificated in metachronous GBM and 7 out of 10 control GBM, which lacked TP53 inactivation as well. Deletion of PTEN occurred only in GBM (6 out of 11). The mismatch repair analysis showed proficiency in DNA samples of all tumors analyzed and germ-line tissue. Analysis of methylation showed common hypermethylation in medulloblastomas and GBMs of BCL2A, BRCA1, FZD9, CDH17, DCN, GLI and MT1A. Genes differentially methylated were FGF1, HDAC6, HOXA, RASSF1, MGMT and TES. Interestingly, hypomethylation of PAX and PTCH gene families were observed in GBM and medulloblastomas.

Conclusions: In our study, extensive molecular investigation at genetic and epigenetic levels pointed to the existence of links between both astrocytic and neuroectodermal tumor entities besides the molecular differences expected.