Fundametal Genetics of Glioblastoma Multiforme

Genetic Etiologies of Glioblastoma Multiforme
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Recent studies in genetic sequencing have found strong causal links between the presentation of select genes and the
presentation of glioblastoma multiforme in mice and humans. Some examples of genes that appear to have a
strong influence on the expression of GBM are illustrated here. Picture from[6]

The importance of understanding the causal factors of gliomas cannot be understated: malignant gliomas account for approximately 70% of all new primary brain tumor cases in the U.S. each year. However, the definition of cancer as an expressed phenotype implies that there must be an interaction between genetic and environmental factors in order for expression of this disease to occur. Since the causes of most cancers are extremely complex, it is necessary to restrict the scope of causal research to primarily genetic causes of one specific type of cancer. An analysis of genetic etiologies for glioblastoma multiforme (GBM) – a specific type of glioma – serves as an effective paradigm for many types of gliomas and has a considerable amount of research available for discussion.

An effective way to discuss genetic pathways responsible for GBM is to classify them according to the number of genes required to create the cancerous phenotype. Some genetic mutations are extremely localized: fusion of two wild-type genes (FGFR and TACC) is sufficient to have a statistically significant effect on the development of GBM: approximately 3.1% of all GBM patients express this genetic defect.[14] On the other hand, for some large gene pathways, oncogenic effects may require multiple defects in order for the development of GBM to occur (often due to the effectiveness of tumor suppressors and other protective mechanisms). Multiple mutations in developmental pathways for particular types of glial cells, including the PDGF/PDGFR pathway, can cause the cells to regress into an earlier (cancerous) form and migrate throughout the body.[2] Therefore, due to the varying “strength” of a specific oncogene, it is extremely important to understand how the effects of an oncogene, or set of oncogenes, can be quantified before an attempt at developing genetic treatments can occur. However, due to the vast array of genetic variations and separate causes of GBM that occur, it will be necessary to restrict the specific examples of single-gene and multi-gene pathways to one paradigm pathway for each category.

Multi-Gene Pathways in Glioblastoma Multiforme

While most cancers are complex diseases which attack normal cell function via a variety of mechanisms, the human body has a host of methods to counteract these malignant conditions. Some forms of GBM arise from a mutation in a very small number of genes (as is illustrated below), but the majority of GBM require multiple mutations in multiple pathways in order for the patient to express the GBM phenotype. This is in no small part due to the fact that often an otherwise carcinogenic mutation will be mitigated by some rescue mechanism of a separate cellular pathway created exclusively to ensure proper cell replication. Therefore, often the appearance of a cancer similar to GBM will require mutations, not only in the main carcinogenic mutation sites, but also in a tumor suppressing or other rescue pathway as well. Described in this section will be an outline of the multiple gene pathways, each of which requires a mutation in order to express the GBM phenotype.

Natural Development and Cancerous Regression of Glial Cells
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The above pictures shows the various stages of development of a glial cell, as well as the location
at which the cell can be found. Normal cell development is shown by a straight line arrow. Normal
development involves pluripotent stem cells (blue), radial glial cells (highly migratory; orange),
neuroblasts (green), and glial restricted progenitor cells (yellow). The x-axis show embryonic life time in
days. Major activating signaling factors are highlighted (note the presence of EGF and PDGFR in various
stages of development). While development of a non-cancerous glial cell continues to develop and
migrate into a fixed position, fully developed cancerous glial cells can regain the proliferation and motile
qualities of radial glial cells (shown by the dashed line near P14)

Example: PDGF/PDGFR, p53, EFG-EGFR Mediated Cell Regression Pathway

Cancerous glial cells responsible for GBM are highly proliferative and highly mobile, much like a developing stem cell. Past research indicates that there are a number of gene pathways (or rather a number of gene pathways that must contain specific mutations) at work in producing select forms of GBM.


A key property of malignant gliomas is the ability of glioma cells to regain stem-cell like motility and proliferative ability. These malignant glial cells often invade other tissues regardless of the severity of the glioma (glioma grade). The method by which these glial cells migrate throughout the brain is extremely similar to the migration of healthy glial progenitor cells, although the origins of these malignant cells are not ventricular-based stem cells, but rather fully differentiated astrocytes. Platelet derived growth factor (PDGF) and the associated platelet derived growth factor receptor (PDGFR) are thought to be critical regulators of this migratory process. The formation of glial progenitor cells and oligodendrocytes during embryogenesis relies heavily on the down regulation of PDGFR-alpha expression.[3] In the adult brain, PDGFR-alpha is restricted to known sites of neurogenesis: the stem cells found in the ventricle and sub-ventricular zones of the lateral ventricles, whereas PDGF is commonly found on most types of mature neural cells.


Action of p53 Gene Product in Carcinogenesis
One of the more well known tumor suppressor genes, the product of p53 is an important
means by which cells prevent carcinogenesis. Loss of function mutations in p53 can
have severe ramifications to cellular integrity, especially if combined with
deleterious mutations in other cell pathways. This video illustrates the structure
and function of p53, as well as some of the more common loss of function mutations
that can occur. Video from [[(bibcite Video))]

Tumor protein 53, or p53 is a protein product of transcription of the TP53 gene which resides in the short arm of chromosome 17. [10] As a tumor suppressor protein, proper function of p53 is extremely important in preventing carcinogenic events from occurring in a wide array of distinct pathways, in a wide array of cancers. in this regard, TP53 is often called the "Guardian of the Genome". Loss of function of P53 is commonly observed in multiple types of gliomas, including anaplastic astrocytomas and secondary glioblastomas. [9] Recent studies into the formation of glioblastomas suggests that the loss of function of the TP53 gene is an early event in the formation of gliomas. [7] As such, the inactivation of P53 is thought to facilitate the high rate of transformation in low-grade glioblastoma cells, contributing to the formation and proliferation of cancerous glial cells. [13] (Please see "Molecular and Protein Pathways in Glioblastoma Multiforme" for an excellent overview of p53 function.)


The expression of epidermal growth factor receptor (EGFR) is commonly seen in high grade astrocytomas; the peak expression commonly correlates with peak gliogenesis.[1] Indeed, the products of the EGFR gene appear to be critical for the progression of an initial low-grade glioma to GBM. The prevalence of EFGR expression in early development, particularly during development of the central and peripheral nervous systems, suggest that EGFR plays a critical role in the development of certain glial cell types, such as astrocytes or oligodendrocytes. The effects of EGF on GBMs appear to be significant; there is evidence that not only is EGFR is fully expressed in GBM cells, but these malignant cells also express EGF causing an autocrine growth stimulatory loop.[3] As well, approximately 40% of GBM instances which express EGFR, express what is called an “activated variant” of EGFR (Such as deltaEFGR, EFGRvIII or del2-7EGFR).[4] Unlike wild type EGFR these mutant variants show significant resistance to down-regulation, implying that the shape of the variant protein is different from the wild-type to the point that the protein cannot adequately express the surface receptors necessary for regular protein function (eg. lysosome degradation). If proteins variants with this loss of protein regulation are present in glioma cells, the instances of tumor formation are found to rise dramatically. [8]

Genetic Defects Necessary to Develop Glioma

It is difficult to precisely quantify the extent to which mutations in the PDGF/PDGFR, p53, and EDGF/EDGFR genes are responsible for the phenotype of GBM, yet it's clear that malformations of these three pathways contribute to the formation of GBM tumors. The regression of a fully formed astrocyte into a malignant cancerous cell with properties similar to a radial glial cell is a complex process which seems to require (among many other things):

  1. Enhanced expression of PDGFR-alpha receptors to promote cell mobility.
  2. Enhanced expression of EGFR to promote glialgenesis and development from low grade astrocytomas to full GBM.
  3. Loss of function of the TP53 gene to prevent protection of normal cellular function.

All three of these factors contribute to the formation of GBM. While it may be possible to induce GBM with a single factor, this is rarely seen; most fully developed GBM cases seem to have some type of malformation in more than one pathway.[2] This is due to the nature of each gene pathway to influence a specific cancer mechanism: PDGFR defects makes cells motile, EGFR promotes glialgenesis, and TP53 acts a general protecting gene. If a cell has a mutation in PDGFR, it may be highly motile but this mutation may be easily suppressed by TP53, or the cell may not reproduce at a threshold rate due to the lack of mutation in EGFR. Therefore, some developmental GBM pathways require mutations in multiple genes in order for the cancer phenotype to be expressed. Identification of these genetic markers may assist doctors in coming to a diagnosis for GBM.

Single Gene Pathways in Glioblastoma Multiforme

Defects in DNA replication, such as the translocations of certain oncogenetic genes, are extremely important in the pathogenesis of cancer. While these translocations can cause activation of gene reproduction effects or deactivation of mutagen-mitigating genes (such as TP53), on rare occasions the translocation of a particular gene will result in the generation of abnormal gene protein product, which itself can interfere will cellular processes associated with division. These “toxic products” can have statistically significant effects on cancer rates, depending on several factors which include the degree of malignancy of the toxic product, the specificity of the toxic product, and the rate at which the toxic product is produced.

Product of Fusion of FGFR-TACC Genes
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Aberrant FGFR-TACC proteins (red) can be seen here localizing to the center of the mitotic cleavage
plane during mitosis. The mutant protein interacts with tubulin (green) to inhibit proper mitotic division of
the two daughter cell nuclei (blue) Picture from Singh et al. via [14]

Example: Fusion of FGFR and TACC Genes

The fusion of genes to produce an aberrant, oncogenetic protein product has been found to be present in a number of different cancers. For example, chronic myelogenous leukemia can result from a constitutively active kinase formed from the fusion of the BCR and ABL1 genes,[12] and the fusion of TMPRSS2 and ERG genes can enhance expression of prostate cancer promoter genes.[15] However, the example that will be discussed in detail, both for its pathway mechanism and its target location, is the fusion of FGFR and TACC genes in GBM.

Pathway Description

An important example of a single gene which has a significant impact on GBM cancer rates (approximately 3% of all GBM are caused at least in some part by this genetic defect) is the fusion of fibroblast growth factor receptors (FGFR) with members of the family of microtubule and chromosome interacting proteins that are commonly activated in cellular mitotic division, called transforming acidic coiled-coil-containing protein (TACC) (although TACC products are also present throughout the cellular cycle). Fusion gene products have been identified before in several types of cancer, including those of the blood, lungs, and prostate[11] but have only recently begun to be studied in neuro-oncological settings. While proteins produced by TACC genes have long been hypothesized to be carcinogenic in several types of human tumors, the mechanism by which these genes fuse with FGFR is a relatively recent discovery (2012). The process of this fusion occurs due to the fusion of the intracellular tyrosine kinase domains of select alleles of FGFR upstream of the TACC allele domains, and produces a faulty toxic protein product which primarily localizes to the mitotic spindles, inhibiting their formation and the process of proper mitotic division. Evidence produced by analysis of split reads and split inserts from exome DNA sequences seem to indicate that the formation of FGFR-TACC is the only statistically significant malformed genomic rearrangement observed in studies by Singh et. al.[14]

Genetic Defects Necessary to Develop Glioma

While it’s clear that the existence of the FGFR-TACC fusion gene promotes a statistically significant increase in cancer, there is considerable interest into the precise method of the oncogenetic effects of the gene fusion produces. The development of cancer can generally be described as an over activation of cellular division, and the vast majority of cancers arise from an inhibition of tumor suppressing products (perhaps the most well-known being the products of the tumor suppressing gene p53); very few have been observed to develop a direct gain of function mutation.[5] Essentially, it seems to be far less common to find an aberrant gene product which directly stimulates carcinogenic effects, than it is to find one that inhibits tumor suppressing genes which repair naturally occurring defects in replication. However, it appears that the FGFR-TACC fusion gene directly initiates tumorigenesis; it may have directly trigger growth-promoting functions in addition to the loss in mitotic stability which is triggered by the aberrant product. This particular type of fusion protein has become one of the prime examples of a gene product which effectively deregulates kinase activity, directly promoting tumorigenesis. As such, there is considerable study into this new oncogenetic mechanism and clinical treatments that could be used to mitigate its effects. Since the aberrant FGFR-TACC protein appears to act as an carcinogenic kinase, sustained inhibition of FGFR was found to prolong the survival of mice with this particular type of GBM.[14]

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