Komotar, Ricardo J.; Starke, Robert M.; Sisti, Michael B.; Connolly, E.
Neurosurgery . 70(6):N22–N23, June 2012.
Oligodendrogliomas comprise approximately 20% of brain tumors in adults, representing the second most common adult brain tumor. These tumors can progress to an anaplastic form, thereby conferring a significantly worse prognosis and poor treatment response. Loss of heterozygosity (LOH) of chromosomes 1p and 19q in oligodendrogliomas provides the best measure of prognosis and response to treatment. The translocation of chromosomes produces marker chromosome (1;19) (q10;p10), and the breakpoints are in gene-poor centromeric areas suggesting a likely unmasking of a tumor suppressor genes.
Recently, Bettegowda et al sequenced the coding exons of 20 687 genes in DNA from 7 anaplastic oligodendrogliomas to better understand possible tumor suppressor genes. The authors identified 225 non-synonymous somatic mutations, affecting 200 genes with an average of 32 non-synonymous somatic mutations. Important mutations encountered in select tumors included PIK3, NOTCH1, and IDH1.
Important mutations in residual copy of the target gene(s) identified that could help elucidate tumor suppressor genes included FUBP1 (Far Upstream Element [FUSE] Binding Protein 1), NOTCH2, and CIC the homolog of the Drosophila capicua gene. FUBP1 and CIC mutations were identified in, respectively, 3 and 12 of 27 additional tumors. The FUBP1 mutations and more than 25% of the CIC mutations were predicted to inactivate their encoded proteins as commonly seen in tumor suppressor genes. To better understand the prevalence of these mutations, the authors sequenced 92 tumors of the nervous system and 206 non-nervous system tumors and found only 3 missense mutations in CIC (breast, prostate, and medulloblastoma) and no truncating alterations.
In Drosophila, the protein encoded by CIC has been shown to be a downstream component of receptor tyrosine kinase (RTK) pathways that includes EGFR, Torso, Ras, Raf, and mitogen-associated protein kinases. In the absence of RTK signaling, cic, blocks transcription by binding to regulatory regions. RTK signaling blocks the function of cic resulting in degradation of cic and the consequent activation of the genes it normally represses. FUBP1 is likely inactivated by mutations leading to MYC activation, a well delineated oncogene.
This genomics study provides a novel view of oligodendroglioma molecular biology with promising clinical utility. It is conceivable that these alterations identify a biologically specific subgroup of oligodendroglioma patients and that new treatments can be designed to take advantage of these alterations. This study demonstrates the value of unbiased genome-wide genetic analyses in the characterization of human brain cancer and identifies a potentially useful genetic alteration for the classification and targeted therapy.
An increasing body of literature supports the utility of expression profiling in stratification of brain tumor patients. Moreover, rational therapeutic targets appear to enhance clinical applicability. Although further investigations are clearly necessary, at this time it is apparent that adjuvant regimens should not be uniform, and that choosing the most efficacious agent for each individual may require routine expression analysis to target susceptible molecular pathways. For instance, expression analysis could be conducted immediately after resection in multiple biopsy samples of core and invasive tumor regions, perhaps identified on preoperative MRI. Implementing expression analysis as a standard clinical test, however, will require significant changes in the way clinicians approach brain tumor treatment, as well as the development of substantial infrastructure for rapid, high-throughput expression and mutation analysis. The subsequent challenge of interpreting this data will require an expansion of expertise from academic studies to wider clinical practice. Despite these obstacles, it is vital to take into account the genetic mutations present in each patient’s tumor before chemotherapeutic agents that target molecular pathways can ever be expected to achieve maximal clinical efficacy. Furthermore, it is important to consider that oligodendrogliomas are composed of a group of related but genetically distinct tumor cells, and capitalize on this knowledge by using therapies that target all populations present in the lesion.