We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Mutations in mouse Mahogunin Ring Finger-1 (Mgrn1) were first recognized for their effect on agouti-mediated pigment-type switching. Mgrn1 null mutants are completely black and develop spongiform degeneration of the brain. Mgrn1 hypomorphs have dark fur but do not develop neurodegeneration. We characterized a new Mgrn1 hypomorphic allele caused by a gene-trap insertion. Mice homozygous for this mutation are slightly darker than non-mutant animals. They show reduced overall expression of Mgrn1 and two of the four normal Mgrn1 isoforms are replaced by beta-GEO fusion proteins that differ from the normal proteins at their carboxy termini. To investigate the role of different Mgrn1 isoforms in pigment-type switching, we used quantitative relative reverse transcriptase polymerase chain reaction to examine their expression in the skin of Mgrn1 mutant and control mice. Most Mgrn1 mutants produce little or no normal Mgrn1 in the skin. Mgrn1 null mutant mice overexpressing isoform I or III, which are normally absent or weakly expressed in adult skin, had normal agouti-banded hairs. Our results indicate that reduced levels of MGRN1 cause the pigmentation phenotypes of Mgrn1 mutant mice and that there are no significant differences in the function of the four MGRN1 isoforms in pigment-type switching.