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Genomics in the Journals Sep 25, 2014

NEW YORK (GenomeWeb) – In Nature Genetics, researchers from the Memorial Sloan Kettering Cancer Center, the Ontario Institute for Cancer Research, the University of Toronto, and elsewhere described recurrent activating mutations in the PRKD1 gene that appear to drive formation of a salivary gland cancer called polymorphous low-grade adenocarcinoma, or PLGA.

The team used RNA sequencing and exome sequencing to assess matched tumor and neighboring normal tissue from three individuals with PLGA. Those analyses did not uncover any noticeably in-frame fusion transcripts. But they did reveal recurrent single nucleotide changes affecting the same amino acid residue of the serine-threonine kinase enzyme encoded by PRKD1.

When they did targeted sequencing on 53 more PLGA samples, the researchers found one of the activating mutations in almost 42 percent of the tumors and the alternative activating change at the same site in more than 30 percent.

In contrast, mutations at the PRKD1 hotspot did not turn up in tests of hundreds of other salivary gland cancers, though mutations at other sites in the gene were reported in a small subset of cancers considered for the Cancer Genome Atlas effort.

As such, those involved in the study speculated that activating mutations at this PRKD1 site "might be employed as an ancillary molecular marker to differentiate PLGA from its more aggressive mimics, including [adenoid cystic carcinoma]."


A team led by Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College investigators conducted an integrative analysis of malignant peripheral nerve sheath tumors (MPNST) to identify recurrent inactivating mutations in genes coding for polycomb repressive complex 2 (PRC2) proteins.

As they reported in Nature Genetics, the researchers did exome sequencing, transcriptome sequencing, copy number analyses, and loss-of-heterozygosity testing on 15 tumor samples collected from a dozen individuals with MPNST. Through comparisons with matched normal samples from the same individuals, they saw an over-representation of loss-of-function mutations affecting PRC2 coding genes such as EED and SUZ12.

In the original sample set, such glitches were documented in 92 percent of tumors from individuals with sporadic MPNST, for example. In radiotherapy-associated MPNST cases, meanwhile, the PRC2 inactivating alterations occurred about 90 percent of the time and some 70 percent of MPNST tumors that were attributed to germline mutations in the NF1 gene (called neurofibromatosis type I MPNST) carried similar changes to PRC2 components.

The analysis also indicated that many of the MPNST tumors — including those not classified as NF1-associated — contained mutations affecting the NF1 and/or CDKN2A genes, prompting the study's authors to argue that "MPNSTs share common molecular pathogenic pathways despite clinical and histological diversity."


An mBio study by researchers at the University of Chicago and the Argonne National Laboratory suggests some patients experience diminished gut microbiome diversity after lengthy stays in intensive care.

The team used 16S ribosomal RNA sequencing to track microbial community members in fecal samples collected from 14 individuals in intensive care units at University of Chicago hospitals over time periods ranging from a few days to more than 30 days. In almost one-third of individuals tested, the composition of gut microbial communities shifted dramatically after intensive care stays, leading to "ultra-low-diversity" gut microbiomes dominated by just a few bacterial genera and families.

In particular, the researchers saw an over-representation of Enterococcus faecium and Staphylococcus aureus bugs in those low-diversity gut communities, as well as microbes from the Enterobacteriaceae family and Candida yeast.

Indeed, in four of the patients, available sequence data revealed gut communities composed primarily of just two main components, a Candida species and a potentially pathogenic bacterial representative. Follow-up experiments in the Caenorhabditis elegans worm model hinted that the bacterial and fungal members of such communities may rein in each others' virulence, though pathogenesis appeared to arise when the balance between them was upset.

Additional research is needed to explore such relationships, according to the study's authors, since such shifts are suspected of increasing sepsis risk and related health problems in a hospital setting.

"[T]he presence of bad guys alone doesn't tell you who's going to live or die," co-senior author John Alverdy, a gastrointestinal surgeon at the University of Chicago, said in a statement. "It's not only which microbes are there, but how they behave when provoked by the harsh and hostile conditions of critical illness."


Human populations living at high altitude sites in Asia and America seem to share some genomic adaptations to these low oxygen locales that have been acquired through convergent evolution, according to a study in the American Journal of Human Genetics.

Researchers based in Switzerland, the UK, and France brought together SNP profiles for 49 individuals apiece from high-altitude populations in Tibet and the Andes, using a new mathematical model to search for signs of local genomic adaptation amongst signals associated with the broader demographic patterns in each population. They also included genotyping data for 39 individuals from a low-altitude Central American population and 90 East Asian individuals living at low altitude.

The analysis uncovered almost 1,200 SNPs showing signs of selection. Of those, 611 variants appeared to be under selection in individuals from Asia, while 186 SNPs seemed to have been selected for in the South American individuals.

The remaining 362 SNPs appeared to have undergone some convergent adaptation, researchers found, sharing selection signals in high-altitude populations from both the Himalayas and the Andes.

Roughly one-third of the convergent sites fit into genome regions genome showing significant ties to high altitude, while the team's gene set enrichment analysis highlighted a potential role for the fatty acid omega oxidation pathway in the high altitude adaptation process.

"The simultaneous analysis of these two geographic areas allows us to identify several candidate genome regions for altitudinal selection, and we show that convergent evolution among continents has been quite common," noted corresponding author Matthieu Foll and his colleagues. Foll was affiliated with the University of Berne and the Swiss Institute of Bioinformatics when the study was done.

"In addition to identifying several genes and biological processes involved in high-altitude adaptation," they added, "we identify two specific biological pathways that could have evolved in both continents to counter toxic effects induced by hypoxia."

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