Glioblastoma molecular subtypes [Neurosurgery Wiki]

This page is read only. You can view the source, but not change it. Ask your administrator if you think this is wrong.
====== Glioblastoma molecular subtypes ======

Integrative [[multi-omics]] using a [[neural network]] identified [[master kinases]] responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, Migliozzi et al. validated [[PRKCD]] and [[DNA-PKcs]] as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and [[radiomics]] features, orthogonally validated by [[proteomics]], [[phospho-proteomics]], [[metabolomics]], [[lipidomics]], and [[acetylomics]] analyses, and recapitulated in pediatric glioma, breast, and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. They developed a probabilistic classification tool that performs optimally with [[RNA]] from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective [[clinical trial]]s
((Migliozzi S, Oh YT, Hasanain M, Garofano L, D'Angelo F, Najac RD, Picca A, Bielle F, Di Stefano AL, Lerond J, Sarkaria JN, Ceccarelli M, Sanson M, Lasorella A, Iavarone A. Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy. Nat Cancer. 2023 Feb 2. doi: 10.1038/s43018-022-00510-x. Epub ahead of print. PMID: 36732634.)).
----

Verhaak et al classified GBM samples based on gene expression into four subtypes, namely classical, mesenchymal, neural, and proneural
((Verhaak RGW, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.)).


[[Classical glioblastoma]]

[[Mesenchymal glioblastoma]]

[[Neural glioblastoma]]

[[Proneural glioblastoma]].

Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed
((Thomas AA, Brennan CW, DeAngelis LM, Omuro AM. Emerging Therapies for
Glioblastoma. JAMA Neurol. 2014 Sep 22. doi: 10.1001/jamaneurol.2014.1701. [Epub 
ahead of print] PubMed PMID: 25244650.
)).

The molecular heterogeneity of [[glioblastoma]] has been well recognized and has resulted in the generation of molecularly defined subtypes. 

The clinical relevance of contemporary molecular classification of gliomas using the routine assessment of IDH mutations, promoter methylation of MGMT, chromosomal deletion of 1p/19q, mutations of EGFR and ATRX genes, and BRAF fusion or point mutation has to be highlighted. 

These subtypes are associated with particular signaling pathways and differential patient survival. Less understood is the correlation between these glioblastoma subtypes with immune system effector responses, immune suppression and tumor-associated and tumor-specific antigens. The role of the immune system is becoming increasingly relevant to treatment as new agents are being developed to target mediators of tumor-induced immune suppression which is well documented in glioblastoma.

To ascertain the association of antigen expression, immune suppression, and effector response genes within glioblastoma subtypes, the [[Cancer Genome Atlas]] Project (TCGA) glioblastoma database has an enrichment of genes within the mesenchymal subtype that are reflective of anti-tumor proinflammatory responses, including both adaptive and innate immunity and immune suppression.

These results indicate that distinct glioma antigens and immune genes demonstrate differential expression between glioblastoma subtypes and this may influence responses to immune therapeutic strategies in patients depending on the subtype of glioblastoma they harbor 
((Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, Dziurzynski K, Gilbert M,
Heimberger AB. Immune Heterogeneity of Glioblastoma Subtypes: Extrapolation from 
the Cancer Genome Atlas. Cancer Immunol Res. 2013 Aug;1(112). doi:
10.1158/2326-6066.CIR-13-0028. PubMed PMID: 24409449.)).

Mitochondrial genome sequence will provide new genetic resource into glioblastoma multiform disease
((Wang XY, Zhang HW, Wang DH, Li XG. Whole mitochondrial genome sequence of a
glioblastoma multiforme model inbred rat (Muridae; Rattus). Mitochondrial DNA.
2014 Oct 28:1-2. [Epub ahead of print] PubMed PMID: 25350734.)).

see http://thejns.org/doi/full/10.3171/2014.9.FOCUS14521