14 Aug 2018
As part of release v86 we have focused on updating the expert-curated mutation data for glioblastoma multiforme (GBM). Approximately 70 additional publications that include mutation screening data in this disease are included in the release.
GBM is the most common malignant primary tumour of the adult brain and has a poor prognosis. It is a high-grade glioma, a WHO grade IV astrocytoma. There have recently been high-profile cases of glioblastoma multiforme (GBM) in the media, including Baroness Tessa Jowell in the UK and Senator John McCain in the USA. You can find GBM in the COSMIC Cancer Browser and view the mutations found in this phenotype.
GBM may occur de novo or develop as a secondary tumour from diffuse astrocytoma WHO grade II or anaplastic astrocytoma WHO grade III. Primary and secondary GBMs have different genetic profiles, with IDH1/2 mutations being evident in secondary GBM. Similarly TP53 mutations are more common in secondary than in primary GBM. The most common mutations in primary GBM are TERT promoter mutations (especially C>T changes at GRCh37 g.1295228 and g.1295250), occurring in 70-80% of tumours, and these mutations are indicative of poorer outcome. Alterations in EGFR are also frequent in primary GBM, with EGFR amplification present in approximately 40% and about half of these cases also carrying the EGFR vIII mutant, an inframe deletion of exons 2-7. Also common in primary GBM are CDKN2A deletions and PTEN mutations. By contrast, paediatric GBM has a different genomic landscape to that of adults, with infrequent changes in CDKN2A, PTEN and EGFR but frequent mutations at hotspot positions in H3F3A and H3.1.
This GBM update includes a paper by Koschmann et al. (COSP42263) who characterise the impact of PDGFRA pathway alterations in paediatric high-grade gliomas (HGG), including GBM, by integrating genomic data from multiple paediatric datasets and sequencing platforms. PDGFRA mutations are found in older paediatric patients and PDGFRA amplification is prognostic in non-brainstem HGG. Also in paediatric GBM, by using genome-wide molecular profiling, Korshunov et al. (COSP45055) note significant molecular heterogeneity in H3-/IDH-wild type tumours in terms of DNA methylation and cytogenetic alterations.
GBM has some rare variants, including gliosarcoma, giant cell GBM and epithelioid GBM; the latter often harbouring BRAF V600E mutations. Gessi et al. (COSP39638) study the heterogeneous genetic background of GBM with unusual lipoblast/adipocyte-like features, while Funata et al. (COSP44879) report a case of osteoclast-like giant cell-rich epithelioid glioblastoma with BRAF V600E mutation.
Current standard treatment for GBM is radiotherapy plus adjuvant temozolomide (TMZ) but survival rates remain very poor, with most cases recurring. Efforts to improve survival with targeted therapies, including inhibition of EGFR and PDGFR, have been unsuccessful. Omura et al. (COSP45329) report a phase IB study of the combination of carboxyamidotriazole orotate (CTO), a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signalling pathways, and different TMZ schedules. CTO combines safely with TMZ or chemoradiation in GBM, and mutations in genes such as TSC2 and PTEN are identified at treatment failure, indicating that combinations with other agents targeting these pathways would be potentially beneficial.