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Kids on the brain
MEMPHIS, Tenn.—In one of the latest studies from the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project (PCGP), a new study of a rare and lethal type of childhood tumor has found that nearly 80 percent of the tumors have mutations in genes previously unconnected with cancer, mutations that evidence suggests factor into other pediatric brain tumors as well. The study, "Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas," was published in the January 29 online edition of Nature Genetics.
Diffuse intrinsic pontine glioma (DIPG), the tumor covered in the study, kills more than 90 percent of patients within two years, and is found nearly exclusively in children. DIPG accounts for 10 to 15 percent of pediatric tumors of the brain and central nervous system. The tumor occurs in the brain stem, and in addition to being inoperable, it has no effective therapies.
"This discovery would not have been possible without the unbiased approach taken by the Pediatric Cancer Genome Project," Dr. Suzanne Baker, corresponding author of the study, said in a press release. Baker is a member of St. Jude's Department of Developmental Neurobiology and co-leader of the St. Jude Neurobiology and Brain Tumor Program. "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."
The cancer and normal genomes of seven patients with DIPG were sequenced for the study originally, with another 43 being sequenced after researchers discovered the high frequency of the mutations. After sequencing all 16 related genes that make related variants of histone H3 proteins in the additional 43 patients, it was discovered that many of the tumors have the same mistakes in only two of those genes.
Researchers discovered that 78 percent of the DIPG tumors studied had mutations in one of two genes belonging to the histone H3 family that contain instructions for making proteins that have similar roles in packaging DNA inside cells. DNA is wrapped around histones so it is compact enough to fit in nuclei, and the packaging influences which genes are switched on or off, the repair of DNA mutations and DNA stability. If any of these processes are disrupted, it can contribute to cancer.
"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," Dr. Richard K. Wilson, director of The Genome Institute at Washington University School of Medicine in St. Louis and one of the corresponding authors of the study, said in a press release. "This is exactly the type of result one hopes to find when studying the genomes of cancer patients."
Sixty percent of the 50 DIPG tumors sequenced had a single alteration in the H3F3A gene, which, when translated into a protein, led to the substitution of methionine for lysine as the 27th amino acid, while another 18 percent had the same mistake in the HIST1H3B gene.
"The amino acid that is mutated most frequently in the DIPGs, which is lysine 27 of H3F3A, is a residue that is modified by a number of different enzymes, and that modification determines whether or not there are transcriptional activators or transcriptional repressors recruited to the DNA of selective regions where that modification happens on this amino acid, to histone 3," says Baker. "And that specific modification is associated, and has been shown previously to be associated, with genes that are really important in differentiation and in development. And so there's a possibility that these mutations have a very specific birth advantage only in the context of a particular developmental stage.
"I think that particularly makes sense for DIPGs, because these tumors are seen almost exclusively in children…I think that this reflects the context of the developing brain, where childhood gliomas develop compared to that in the adult brain," she adds.
While mutations in enzymes that target histone H3 have been seen in other cancers, this is the first case of a specific alteration of histones. H3F3A and HIST1H3B were also mutated in glioblastoma tumors, with 36 percent of the 36 glioblastoma tumors carrying one of three distinct point mutations in the genes, as well as a single change in H3F3A's makeup not seen in DIPG tumors. Otherwise, the H3 alterations are not seen in other cancers, not even adult glioblastoma.
"The high frequency of these mutations, 78 percent, suggests that this extremely important for the tumor to have this mutation in order to become a DIPG," says Baker. "So that makes us hopeful that if we could devise a way to target or counteract this mutation, that it might have a very, very big effect on the survival or the growth of DIPG tumors. Now exactly what that intervention would be is not yet clear, so really the next avenue of research will be to try to understand exactly how these mutations contribute to tumor formation and growth. "
The first authors of the study are Gang Wu, Alberto Broniscer and Troy McEachron, and the other corresponding authors are Jinghui Zhang and James Downing, all of St. Jude. Additional study others include Charles Lu, Li Ding and Elaine Mardis, from Washington University, and Barbara Paugh, Jared Becksfort, Chunxu Qu, Robert Huether, Matthew Parker, Junyuan Zhang, Amar Gajjar, Michael Dyer, Charles Mullighan, Richard Gilbertson and David Ellison, from St. Jude.
Funding came in part from the PCGP, including lead project sponsor Kay Jewelers, as well as from the National Institutes of Health, the Sydney Schlobohm Chair of Research from the National Brain Tumor Society, the Cure Starts Now Foundation, Smile for Sophie Forever Foundation, Tyler's Treehouse Foundation, Musicians Against Childhood Cancer, the Noyes Brain Tumor Foundation and ALSAC.