Geneb MYC MYCN MYCN aThe mutation data were obtained from the Sanger Institute Catalogue of Somatic Mutations in Cancer web site (as of October, 2011), http:// www.sanger.ac.uk/cosmic (105), in the Primary Tissue category of Central Nervous System (CNS) tumors. bFor MYC, one mutation was found in 524 cases examined in the category of CNS tumors. For MYCN, two mutations were found in 469 cases examined in the category of CNS tumors. No mutations were reported for MYCL1 in the category of CNS tumors (45 cases). WHO = World Health Organization; AA = amino acid; CDS = coding sequence; TCGA = The Cancer Genome Atlas (51). Sample name TCGA-02-0083 TCGA-02-0010 TCGA-02-0028 Sample ID 1287236 1287210 1287216 Histology (WHO grade) Glioblastoma (IV) Glioblastoma (IV) Glioblastoma (IV) 126 F. J. Swartling Table I. Few mutations of Myc genes are found in brain tumor samplesa. AA mutation CDS mutation p.R316R p.P365P p.P44L c.948G > A c.1095A > G c.131C > T However, whether TRIM32 can also regulate prolif- eration by differentiating brain tumor cells is currently not known. Myc mutants A mutation causing a switch from threonine to alanine on residue 58 was discovered in the transforming v- myc viral gene and in Myc or Mycn in Burkitt’s lymphoma patients (103,104). This mutation pre- vents the phosphorylation from GSK3b that is so important for Fbw7 recognition which can lead to proteolytic degradation of Myc proteins. When searching the Catalogue of Somatic Mutations In Cancer (COSMIC) (105), very few mutations for Myc genes are found in the category of central ner- vous system (CNS) tumors (Table I). Here, only one mutation in MYC and two (with one being a silent mutation) in MYCN were reported (from The Cancer Genome Atlas (TCGA) genotyping screen (51)). Whether any of the non-silent mutations (Table I) could affect Myc protein function or stability has not been reported. Myc and Ras collaborate to transform cells Expression of c-myc together with a co-operative oncogene like Ras is necessary for the stable trans- formation of primary or early-passage ﬁbroblasts (106). Ras can stabilize Myc proteins in tumors. One example is through high ERK-mediated Myc S62 phosphorylation in Ras-transformed cells (83). Different activating mutations of Ras promote ERK- mediated phosphorylation and are implicated in brain tumors, but it is important to distinguish if and how the different isoforms collaborate with Myc proteins in brain tumor formation and maintenance. For example, H-rasG12V can collaborate with v-myc to generate brain tumors in human fetal neural stem cells (23), but H-rasQ61L cannot help v-myc to gen- erate brain tumors in human adult neural stem cells in another report (107). It is possible that fetal neural stem cells are more prone to transformation than adult neural stem cells or that the different activating mutations have different effects on brain tumor devel- opment. Myc proteins might require different isoforms of Ras proteins as collaborators in brain tumorigen- esis. For example, when searching COSMIC (105) there are reports of mutations in CNS tumors (like glioma and PNETs) only for N-ras (8/1017) and K-ras (8/1054), but not for H-ras (108). Mutations found in K-ras and N-ras were at residues 12 or 61. For N-ras it is evident that all mutations at residue 12 (4/1017) were found only in glioma samples, while mutations at residue 61 (4/1017) were found only in PNET or medulloblastoma. Interestingly, in the Myc- Ras collaboration, Myc represses the cellular senes- cence induced by Ras. This repression of senescence by Myc requires phosphorylation of Myc at S62 by the cell cycle kinase Cdk2 that is needed for inhibiting cellular senescence induced by c-myc (109,110). Many oncogenes like Ras (22,23), Akt (22), Shh (17), or beta-catenin (21) can be involved in collab- orating with Myc proteins to induce brain tumors. This property of Myc proteins to launch collabora- tions during tumor formation warrants more high- throughput screens in order to identify critical Myc collaborating genes using previously successful strat- egies with retroviral tagging (111,112) or Sleeping Beauty techniques (113–116) in mice. How can we inhibit Myc proteins in brain tumors? Many tumors show addiction to Myc oncoproteins (117). This is also true in Mycn-driven medulloblas- toma models in which inhibition of Mycn will result in total tumor regression and cellular senescence (20). In glioma where suppressor genes like p53 and Pten are inactivated, c-myc is essential for tumor mainte- nance, and c-myc inhibition will suppress tumors by promoting differentiation of the glioma cells (60). It is evident that Myc proteins are validated targets for cancer therapies (as reviewed in (118,119)).