Monday, 23 April 2012


The Incurable Brain Cancer? – Perhaps not...

Sam Bennett - 42899697
Figure 1: An MRI showing a GBM (Medscape, 2011)
Many people think of cancer as one of the evils of the earth, the incurable killer of friends and family and they are correct, partially. It is an ugly disease that can either slowly or quite quickly kill the affected, leaving them a shell of their former self just before death. However, while cancer does not have a cure, it can be encouraged into remission, or physically removed from the patient. However, one particular case of brain cancer, Glioblastoma multiforme, also known as GBM, is particularly ruthless when seen in younger patients. It is puzzling that adults affected with this type of tumour can sometimes recover, yet children almost never survive.

When children are affected by GBM, the tumours are extremely unresponsive to traditional chemotherapy and radiotherapy treatment, despite them being “morphologically indistinguishable from their adult counterparts”, meaning, that basically, their structure is identical (Jeremy Schwartzentruber, 2012). However, considering that the cancer reacts differently to fundamental treatments, it appears that paediatric GBM must be genetically coded differently to the GBM that appears in adults. It is this inference that a research team of the McGill University Health Centre acted upon, and made some very significant findings.

The team undertook a thorough analysis on the mutation in the protein-coding genes by sequencing the exomes - part of the genome - of 48 samples of GBM taken from patients aged from 3 to 20 years old (Jeremy Schwartzentruber, 2012). The team found genetic mutations totalling between 3 and 31 in each tumour, however it was two reoccurring mutations in the gene known as histone H3.3 (Jeremy Schwartzentruber, 2012). These mutations in H3F3A and ATRX, as well a mutation in the gene DAXX, which works very closely with ATRX in H3.3 recruitment, were analysed and found to be present in 44% of samples (Jeremy Schwartzentruber, 2012).

The results indicated that H3F3A mutations were at lease fairly exclusive to paediatric GBMs, as the 22 adult GBM samples sequenced earlier contained no mutations. To confirm this, the team sequenced 784 glioma samples – GBMs are a specific subset of gliomas – of no specific selective criteria and found that 32/90 paediatric samples contained the mutation (Jeremy Schwartzentruber, 2012) (Medscape, 2011).
Figure 2: A comparison of the most frequently mutated genes in paediatric and adult GBM (Jeremy Schwartzentruber, 2012)
The discovery of the mutations of the histone H3.3 gene is such an important discovery because of the specific function of H3.3 and the fact that the outcome of children diagnosed with GBM is so dismal. Histone H3.3 is a fundamental gene for regulating the accessibility of DNA, and also plays a role in “transcription regulation, DNA repair, DNA replication and chromosomal stability” of cells. (UniProtKB, 2012).  It is a key gene in DNA replication, and hence if mutated it prevents “cells from differentiating normally and helps protect the genetic information of the tumour”, according to Dr. Nada Jabado of The Montreal Children’s Hospital (Science Daily, 2012). It is this fact that the mutated gene protects the genetic information of the tumour that explains why the strain of GBM in children is so resistant to chemotherapy and radiotherapy.

With this knowledge and by explaining why conventional treatment has been so ineffective in child cancer patients, doctors can begin to concentrate on the treatment of the correct source of the cancer rather than futilely treating the cancer using methods that in reality are for something quite different. For the bigger picture, including other cancers, this study is the first which shows a mutation in a gene that is meant to protect the genetic code of the body, and by doing so proves that cancer can be caused by a modified genome.

Bibliography

Jeremy Schwartzentruber, A. K. &. X.-Y. L., 2012. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. NATURE.
Medscape, 2011. Glioblastoma Multiforme. [Online]
Available at: http://emedicine.medscape.com/article/283252-overview
[Accessed 19 March 2012].
Science Daily, 2012. Genetic Breakthrough for Brain Cancer in Children. [Online]
Available at: http://www.sciencedaily.com/releases/2012/01/120130102522.htm
[Accessed 19 March 2012].
UniProtKB, 2012. Histone H3.3. [Online]
Available at: http://www.uniprot.org/uniprot/P84243
[Accessed 19 March 2021].



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