A recent study published in the online edition of the scientific journal Nature Genetics of rare, lethal childhood tumors of the brainstem has revealed that almost 80% of tumors contain gene mutations that have previously not been associated with cancer. According to early evidence, gene alterations also implicate other aggressive pediatric brain tumors. The results provide a significant insight into a poorly understood tumor that has a mortality rate of over 90% in patients within two years.
Almost exclusively prevalent in children, the tumor called diffuse intrinsic pontine glioma (DIPG), an extremely invasive tumor that occurs in the brainstem at the base of the skull and controls such vital functions as breathing and heart rate, accounts for 10 to 15% of pediatric tumors of the brain and central nervous system. It is accurately diagnosed by non-invasive imaging and cannot be cured by surgery, which means that knowledge so far is limited as it is rarely biopsied in the U.S.
Study author Suzanne Baker, Ph.D., co-leader of the St. Jude Neurobiology and Brain Tumor Program and a member of the St. Jude Department of Developmental Neurobiology commented:
"We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies."
Cancer is caused by a disruption of normal gene activity, enabling an unconstrained growth and spread of unchecked cells, which make the disease so lethal.
The study findings showed that 78% of the DIPG tumors displayed changes in one of two genes that both belong to the histone H3 family of proteins, which hold instructions for producing proteins that play comparable roles in packaging DNA inside cells. In order to fit into the nucleus, the DNA must be wrapped around histones to make it sufficiently compact and depending on how the histones package the DNA, the genes are either switched on or off.
The same applies to repairing DNA mutations and for maintaining their stability. A disruption of any of these processes potentially contributes to the development of cancer. According to the researchers, the mutations appear unique to aggressive childhood brain tumors.
Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis and one of the study's corresponding authors declared:
"It is amazing to see that this particular tumor type appears to be characterized by a molecular 'smoking gun' and that these mutations are unique to fast-growing pediatric cancers in the brain. This is exactly the type of result one hopes to find when studying the genomes of cancer patients."
The results from the Pediatric Cancer Genome Project (PCGP), at the St. Jude Children's Research Hospital at Washington University, are the latest from an ambitious three-year endeavor of sequencing complete normal and cancer genomes of 600 children who have some of the most poorly understood and aggressive pediatric cancers.
The human genome contains the entire set of instructions required to construct and sustain human life. The aim of the PCGP is to detect variations that explain the development, spread and deadly impact of cancer in the quest of finding new diagnostic tools and methods for the treatment and prevention of the disease.
In their study, the researchers sequenced the complete normal and cancer genomes of seven patients with DIPG. Baker said:
"The mutations were found at such high frequency in the cancer genomes of those seven patients that we immediately checked for the same alterations in a larger group of DIPGs."
After sequencing all 16 of the related genes, which make closely related variants of histone H3 proteins in an additional 43 DIPGs, they discovered that many of the tumors contained the same mistakes in only two of these genes.
They found that 60% of the 50 DIPG tumors included in this study contained a single alteration in the makeup of the H3F3A gene and observed that during the translation of the mutated gene into a protein, the point mutation resulted in lysine being substituted with methionine as the 27th amino acid in this variant of histone H3 protein. The researchers discovered 18% of the DIPG patients also carried the same mistake in a different gene, in HIST1H3B.
The researchers now explore to understand what role the mutations in H3F3A and HIST1H3B have in terms of cell function and contribution to cancer. Some clues are provided through previous research said Baker, explaining that the mutated lysine is usually targeted by enzymes that attach other molecules to histone H3, which influences the way in which it interacts with other proteins that regulate gene expression.
Even though in other cancers mutations in the enzymes that target histone H3 have been also been detected, this is the first report that demonstrates a specific alteration of histones in cancer. In other aggressive childhood brain tumors, such as glioblastoma, which develops outside the brain stem.
H3F3A and HIST1H3B have also been mutated. The researchers discovered that from 36% of 36 such tumors in this study had one of three distinct point mutations in the genes, which included another single alteration in the makeup of H3F3A that has not been found in DIPGs.
The findings showed however, that any of the other 252 examined childhood tumors, including low-grade gliomas brain tumors, such as medulloblastomas and ependymomas as well as other cancers outside the brain and nervous system, had no mutations of the histone H3 genes. There have been no reports of H3 changes in any other cancers, including adult glioblastoma.
"This suggests these particular mutations give a very important selective advantage, particularly in the developing brainstem and to a lesser degree in the developing brain, which leads to a terribly aggressive brain tumor in children, but not in adults. This discovery would not have been possible without the unbiased approach taken by the Pediatric Cancer Genome Project. The mutations had not been reported in any other tumor, so we would not have searched for them in DIPGs. Yet the alterations clearly play an important role in generating this particular tumor."
Written by Petra Rattue