Primary Brain Tumour Caused by Gene Fusion
By Alexandra Leslie
Brain tumours can be classified into two main categories, primary and secondary tumours. Primary brain tumours are cancers which originate in the brain and rarely spread to other areas of the body; whereas secondary brain tumours are cancers which originate elsewhere in the body, for example the lungs, and spread to the brain. Around 50% of primary brain tumours originate in the glial cells, which are specialised nerve cells, in the brain. Tumours that originate from these cells are called gliomas and the most common gliomas develop from glial cells called astrocytes (Medifocus, 2012). The World Health organisation (WHO) has devised a system for categorising astrocytoma (tumours which develop from astrocytes) into 4 categories, ranging from I (slowest cell division) to IV (most rapid cell division) (Tatter, n.d.).
A Glioblastoma, or Glioblastoma Multiform, is a grade IV astrocytoma (National Brain Tumour Society, 2011) and is one of the most common and lethal forms of primary brain cancer (Singh et al, 2012). A recent study by Columbia University’s Medical Centre (CMUC) has found that the fusion of two adjacent genes in the brain can lead to this highly aggressive form of brain tumour. The research team examined 97 brain glioblastomas and found that 3 of these harboured the fusion of the FGFR gene (fibroblast growth factor receptor gene) (FGFR1 or FGFR3) and the TACC gene (transforming acidic coiled-coil gene) (TACC1 or TACC3). The fusion of these two adjacent genes creates a protein which latches onto the spindle fibres (or mitotic spindle) during mitosis. This interference with the spindle fibres results in the daughter cells containing different numbers of chromosomes (Krakauer, 2012). This chromosomal mutation, where the cells chromosome number is abnormal, is referred to as aneuploidy and is a common cause of cancer.
Image 1. Depicts the fusion of the FGFR and the TACC genes
The CMUC researchers then went on to test their findings on mice. The injected the FGFR-TACC fused genes into the brain cells of healthy mice. As expected, glioblastomas developed in 90% of the mice tested (ScienceDaily, 2012). Following from these findings, the researchers then injected a FGFR kinase inhibitor into the brain cells of half of the mice that had developed glioblastomas. These mice were found to have double the lifespan of the mice who did not receive the FGFR kinase inhibitor. The FGFR kinase is an enzyme which is essential for the production of the FGFR-TACC protein, and when this kinase is inhibited, abnormal mitosis is also inhibited.
This discovery could lead to treatment for cancer patients and could lead a pathway for cancer research. "This is a very exciting advance in our understanding of cancer, and perhaps a first step toward a personalized, precision approach to the treatment of glioblastoma," said Stephen G. Emerson, MD, PhD, director of the HICCC (ScienceDaily, 2012).
Krakauer, H. (2012). Gene fusion is behind deadly brain cancer. In New Scientist. Retrieved August 18, 2012, from http://www.newscientist.com/article/dn22111-gene-fusion-is-behind-deadly-brain-cancer.html
Medifocus. (2012). Medifocus Guidebook on Glioblastoma. In Medifocus. Retrieved August 22, 2012, from http://www.glioblastoma-guidebook.com/2009/landinge.php?gid=OC009&?a=a&assoc=Google&keyword=glioblastoma
National Brain Tumour Society. (2011). Glioblastoma Multiform (GBM). In National Brain Tumour Society. Retrieved August 22, 2012, from http://www.braintumor.org/patients-family-friends/about-brain-tumors/tumor-types/glioblastoma-multiforme.html?gclid=CLuRx_HH-LECFQlLpgod4XAAxA
ScienceDaily. (2012). Genetic Cause of Most Lethal Brain Tumour Pinpointed: May Lead to New Treatment. In ScienceDaily. Retrieved August 16, 2012, from http://www.sciencedaily.com/releases/2012/07/120726142041.htm
Singh, D et al. (2012). Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma. In Science Magazine. Retrieved August 18, 2012, from http://www.sciencemag.org/content/early/2012/07/25/science.1220834.abstract
Tatter, S. (n.d.). The new WHO Classification of Tumour affecting the Central Nervous System. In Massachusetts General Hospital. Retrieved August 21, 2012, from http://neurosurgery.mgh.harvard.edu/newwhobt.htm