Every time a cell divides all the DNA in our bodies must be copied and transmitted. The replication of DNA is imperfect and minor mistakes accumulate with repeated cell divisions over time. These mistakes, known as mutations, are generally unimportant and have no effect on health, but occasionally, some unlucky combination of genetic mutations can lead to cancer. All cancers, including brain tumours, have multiple mutations which act together to drive uncontrolled cell division. Teasing apart how these genetic mutations work alone, and in combination, is the most important part of developing and improving treatment strategies for cancer.
Our lab has a longstanding interest in a protein (called ATRX) which is frequently ‘turned off’ in brain cancers. In our latest study, we looked for other genes which were repeatedly mutated in combination with ATRX and tried to understand how these mutations act together to cause brain tumours. We investigated a structure called a histone, that stores DNA, and a specific change/mutation (known as H3.3 G34R) that is seen in paediatric glioblastomas, and a gene called IDH1 in adult low-grade gliomas. We found that changes in either the histone, ATRX or the IDH1 gene have the same result, they all act on the telomeres.
Telomeres are a long stretches of repetitive DNA found on the ends of chromosomes. Telomeres shorten with every round of DNA replication and act as natural biological clocks to limit the number of cell divisions, i.e. once the telomeres are gone the cell can’t divide anymore. We found that these combinations of genetic mutations (ATRX, H3.3 G34R and IDH1) create a unique environment at the telomeres which allows brain tumours to escape this biological clock, and keep growing.
Although these findings are not immediately applicable to therapy, these fundamental insights into brain cancer biology are critical for developing future treatments. If we know that certain mutations create environments which keep cancer cells alive, then it stands to reason that disrupting those conditions will trigger tumour death. We are currently experimenting with ways to disrupt the telomere environment and the telomeres themselves in human brain cancer cells, and we hope that this publication will encourage other researchers to do the same. We are indebted to The Brain Tumour Charity for supporting this work and we are excited to be able to continue our research into this area.