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Genomics in the Journals: Apr 4, 2013

NEW YORK (GenomeWeb News) – In The Lancet, UK researchers reported on a whole-genome sequencing-based study of multi-drug resistant Mycobacterium abscessus transmission among individuals with cystic fibrosis. Results of the study indicated that some forms of this non-tuberculous mycobacterium — which can cause chronic lung infections in individuals with existing inflammatory conditions affecting the lungs — are often passed from one cystic fibrosis patient to the next.

With genome sequences from 168 M. abscessus isolates collected from 31 individuals with cystic fibrosis at a Cambridge lung infection clinic during the course of about four years, for example, investigators determined that two outbreaks had occurred at the center involving distinct, but genetically similar, M. abscessus isolates. Isolates transmitted during the outbreaks belonged to an M. abscessus sub-species called massiliense, they noted, which appear capable of swapping key antibiotic resistance genes with one another.

"The finding of frequent M. abscessus subsp. massiliense transmission in patients with cystic fibrosis raises several important questions about current infection control measures used in treatment centers," Wellcome Trust Sanger Institute researcher Julian Parkhill and co-senior author Andres Floto, from the University of Cambridge Institute for Medical Research, and their colleagues concluded.

In particular, they pointed to a need for considering "the potential for cross-infection in other patient groups and with other [non-tuberculous mycobacterium] species, and whether mandatory notification of infections with M. abscessus complex and routine whole-genome sequencing might be required to identify and control the spread of these organisms."

Studies by two independent research teams reporting in Nature Genetics implicated the same gene, DEPDC5, in multiple forms of focal epilepsy, a group of seizure-causing conditions that seem to stem from glitches affecting particular brain areas.

In the first of the studies, an international team led by investigators in Australia used exome sequencing to look for mutations involved in an autosomal dominant form of focal epilepsy known as familial focal epilepsy with variable foci, or FFEVF. Based on exome sequencing data from individuals belonging to FFEVF-affected families from Australia and the Netherlands, that research group narrowed in on DEPDC5 — a gene that resides in a stretch of chromosome 22 previously implicated in FFEVF through linkage studies.

When they screened for changes to DEPDC5 in members of six other large families affected by FFEVF, investigators found DEPDC5 mutations segregating with the disease in five of the families. And in another 82 small families affected by FFEVF, they unearthed DEPDC5 mutations in 10 individuals, or 12 percent of the families.

"The identification of DEPDC5 as the gene underlying FFEVF substantially advances understanding of the pathogenesis of epilepsy by implicating another new gene pathway," the University of Melbourne's Ingrid Scheffer, senior author on the study, and her co-authors wrote.

"Apart from enabling the diagnosis of FFEVF through molecular testing," they added, "these findings also enable strategies to be devised to improve prognosis through tailored treatment targeting DEPDC5."

Meanwhile, researchers from France, Switzerland, and Germany tied DEPDC5 mutations to an even broader swath of focal epilepsies that included not only FFEVF but also autosomal dominant frontal lobe epilepsy and familial temporal lobe epilepsy in their own Nature Genetics study.

There, investigators started by doing linkage analyses on two large multiplex French families affected by FFEVF, followed by exome sequencing on affected individuals from one of the families. The search led to a frameshift mutation in DEPDC5, they reported, while targeted sequencing of the gene in 15 more families with various forms of focal epilepsy uncovered four other nonsense mutations and one missense mutation in the gene.

From their findings, authors of that study argued that DEPDC5 "is a common genetic actor in epileptic syndromes with different brain localization and electroclinical expression, including [autosomal dominant frontal lobe epilepsy], [familial temporal lobe epilepsy], and FFEVF."

A Harvard Medical School team has come up with a new scheme for snatching circulating tumor cells out of the bloodstream. As they reported in Science Translational Medicine, the researchers designed a microfluidics platform that uses magnetic labeling and a cell-positioning process called inertial focusing to find tumor cells in the bloodstream. The resulting chip, dubbed CTC-iChip, appears capable of capturing cancer cells based on tumor cell surface markers. But it can also narrow in on circulating cancer cells in the absence of information on tumor antigens through steps that remove red and white blood cells from a given sample, leaving tumor cells behind.

In proof-of-principle experiments, for instance, investigators showed that they could use the CTC-iChip to nab circulating cancer cells in blood samples from individuals with several different types of metastatic cancer, including prostate cancer, breast cancer, pancreatic cancer, and melanoma.

"We're only beginning to identify potential applications of the ability to analyze how tumors mutate as they spread," senior author Mehmet Toner, BioMicroElectroMechanical Systems Resource Center director at the Massachusetts General Hospital's Center for Engineering in Medicine, said in a statement, "but this should help improve our understanding of the fundamental genetic principles of metastasis."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.