Alterations in the ACVR1 Gene can contribute to a Rare, typically Fatal Form of Childhood Brainstem Cancer called Diffuse Intrinsic Pontine Glioma (DIPG).
Reporter: Aviva Lev-Ari, PhD, RN
Nature Genetics studies by several independent research teams indicated that alterations in the ACVR1 gene can contribute to a rare, typically fatal form of childhood brainstem cancer called diffuse intrinsic pontine glioma (DIPG).
Researchers from the University of Toronto, Duke University, and elsewhere used genome or exome sequencing — coupled with array-based methylation, copy number, and gene expression profiling — to assess matched tumor and normal samples from three-dozen children with DIPG.
The analysis defined three DIPG sub-groups: tumors containing previously detected histone alterations, tumors marked by hyper-methylation, and so-called “silent” tumors with low mutation rates. It also revealed activating ACVR1 mutations in roughly one-fifth of DIPG tumors, which appeared to prompt downstream signaling activity that ultimately impacts ID1 and ID2 gene activity.
A team led by investigators in the UK and France saw recurring activating ACVR1 mutations in a similar proportion of DIPG cases in its whole-genome or –exome sequencing study of 26 DIPG samples.
Meanwhile, members of the St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project picked up on ACVR1 mutations in almost one-third of the DIPG cases they profiled by whole-genome, whole-exome, and/or transcriptome sequencing.
The Pediatric Cancer Genome Project team assessed samples from 127 individuals with pediatric high-grade glioma, including 57 DIPG cases and 70 cases of non-brainstem high-grade glioma. Along with the ACVR1 alterations and mutations in genes previously linked to high-grade glioma, the analysis revealed gene fusions in almost half of the DIPGs and non-brainstem high-grade gliomas tested.
Moreover, the majority of high-grade gliomas assessed in that study appeared prone to mutations affecting genes from a receptor tyrosine kinase signaling pathway and/or pathways involved in histone modifications, chromatin remodeling, and cell cycle regulation.
In another Nature Genetics study, a Dana-Farber Cancer Institute- and McGill University-led team linked recurrent, activating ACVR1 mutations to a distinct but similarly difficult to treat childhood brain cancer called pediatric midline high-grade astrocytoma, which is also marked by frequent histone alterations.
By profiling mutation, copy number, and epigenetic patterns in dozens of midline high-grade astrocytomas not been exposed to treatment, the team narrowed in on recurrent alterations in ACVR1 and in the FGFR1 gene that seem to occur in conjunction with different histone glitches.
As such, authors of the study noted, the analysis “considerably expands the number of potential treatment targets and further justifies pre-treatment biopsy in pediatric [midline high-grade astrocytoma] as a means to orient therapeutic efforts in this disease.”
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.