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Genomics in the Journals: Apr 10, 2014

NEW YORK (GenomeWeb News) – In the early, online edition of Science, researchers from China, Denmark, and Saudi Arabia reported on recurrent mutations identified in individuals with adrenal Cushing's syndrome, a condition characterized by benign or malignant adrenocortical tumors or hyperplasias that produce excess amounts of glucocorticoid hormones.

By doing whole-exome sequencing and/or RNA sequencing on samples from dozens of individuals with various forms of adrenal Cushing's syndrome, the team narrowed in on new and known mutations in the Cushing's-related tumors or hyperplasias.

Among them was a previously undescribed hotspot in the PRKACA gene that was mutated in more than 65 percent of those with Cushing's caused by cortisol-producing adrenocortical adenoma tumors. That mutation appeared to boost PRKACA's activity, the researchers reported, leading to phosphorylation of proteins targeted by the PKA enzyme encoded by PRKACA.

The study's authors also saw other recurrent genetic glitches in cases of adrenal Cushing's syndrome involving different types of tumors or hyperplasias, including forms of the disease stemming from specific adrenocortical hyerplasias or from masses known as oncocytomas.

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."

Bird conservation could be aided by a greater phylogenetic focus, according to a Current Biology study. Researchers from the US, UK, Canada, and Australia looked at the relationship between bird species' positions on a phylogenetic tree, evolutionary distinctiveness, and geographic range.

Using such features, they began narrowing in on species that appear to be both evolutionarily diverse and prone to potential extinction threats, defined with the help of a so-called "evolutionary distinctness," or ED, metric.

From a genetic diversity and distinctiveness perspective, for instance, the study's authors argued that particular efforts should be placed on preserving the oilbird and hoatzin, South American birds belonging to distinct branches of the bird phylogenetic tree. Other species popped out of the analysis as well, including Madagascar's cuckoo roller, the frogmouth from the Solomon Islands, and the New Caledonian owlet-nightjar.

"Our approach identifies how spatially and phylogenetically informed prioritization can maximize the extent of the tree of life that can persist into the future," senior author Arne Mooers, a biology researcher with Simon Fraser University's Mathematical and Computational Sciences Centre, and colleagues wrote.