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Genomics in the Journals May 15, 2014

NEW YORK (GenomeWeb) – Two research teams reported on mutational patterns present in gastric cancer in Nature Genetics.

Researchers from the US, Hong Kong, the UK, and the Netherlands did whole-genome sequencing on matched tumor and normal pairs from 100 individuals with gastric cancers from various subtypes and presentations, including microsatellite instable tumors, microsatellite stable tumors, diffuse tumors, gland-forming adenocarcinomas, and so on.

Along with array-based gene expression, copy number, and methylation analyses of the samples, the sequences offered researchers a look at the most frequently altered genes across the tumor set and in certain subtypes.

For instance, they found RHOA mutations in more than 14 percent of gastric cancers from the diffuse tumor type, where particular portions of the gene were especially prone to mutation, causing problems with related signaling processes. On the other hand, gland-forming tumors from the intestinal gastric cancer type did not contain the recurrent mutations in RHOA.

The analysis revealed other new and known driver genes in gastric cancers as well, including genes from adherens junction, focal adhesion, and other pathways. It also highlighted epigenetic differences between tumors from gastric cancers associated with Epstein-Barr virus infection and those characterized by microsatellite instability.

"This study depicts a genomic landscape that highlights the multidimensional perturbations in the gastric cancer genome and epigenome, which occur to an extent seldom seen in other solid cancers," they study's author wrote, "and provides a comprehensive road map to facilitate genome-guided patient stratification and personalized therapy in the near future."

An independent team from Japan found recurrent mutations in the same RHOA gene by focusing specifically on samples from individuals with diffuse-type gastric carcinoma.

After identifying an over-representation of non-synonymous mutations through exome sequencing of tumor-normal pairs from 30 individuals with diffuse-type gastric carcinoma, the researchers turned to more targeted validation sequencing in another 57 cases.

All told, that group saw RHOA mutations in more than one-quarter of the diffuse-type gastric carcinoma cases, again occurring in highly conserved mutation hotspots.

In another Nature Genetics study, an international team described genetic variants contributing to hundreds of metabolic traits based on an association study of more than 7,800 individuals of European ancestry whose metabolite levels were worked out by chromatography and mass spectrometry.

Using serum and/or plasma information for 529 metabolites of interest in the individuals and array-based SNP profiles, the team identified ties between blood levels of more than 400 metabolites and 145 genetic loci, including 84 sites not associated with metabolic patterns in the past.

Those associations were considered in the context of gene expression profiles, disease risk loci, heritability, and other factors, the study authors explained. They also compiled the gene-metabolite information into a freely available resource for other researchers, known as the Metabolomics GWAS Server.

The population of methicillin-resistant Staphylococcus aureus (MRSA) causing epidemic infections in the UK is also circulating in dogs and cats in the region, according to a study in mBio.

Researchers from the University of Cambridge and elsewhere did whole-genome sequencing on a collection of MRSA isolates from four cats and 42 dogs treated at veterinary hospitals in the UK. They noted that the bugs all belonged to multi-locus sequence type ST22, which is associated with most of the epidemic MRSA cases transmitted in UK hospitals.

The team's subsequent phylogenetic analysis of SNPs in the MRSA genomes obtained from dog and cat samples uncovered clustering between isolates from humans and their pets, hinting that MRSA can get transmitted between the two.

Nevertheless, there were subtle differences between the animal and human isolates. For example, human isolates were more apt to carry a plasmid associated with resistance to the antibiotic erythromycin, which is rarely used in veterinary hospitals in the area. When the plasmid did turn up in animals, the study's authors noted, it typically contained mutations implicated in resistance to an antibiotic that is frequently used by veterinarians in the UK.

The study "furthers the 'one health' view of infectious diseases that the pathogens infecting both humans and animals are intrinsically linked," corresponding author Mark Holmes, a veterinary medicine researcher at the University of Cambridge, said in a statement, "and provides evidence that antibiotic usage in animal medicine is shaping the population of a major human pathogen."

A team from Denmark, the US, Canada, and Mexico included mitochondrial DNA analyses in its efforts to characterize an ancient human skeleton found in an underwater cave in Mexico's Yucatan Peninsula.

As they explained in Science, the researchers considered craniofacial features, mitochondrial haplotype data, and other characteristics of the skeleton, which came from a 15- or 16-year-old girl and is believed to be between 12,000 and 13,000 years old.

The individual carried mitochondrial sequences from the D1 haplogroup, consistent with Beringian population ancestry that's shared with Native American populations. But her skull, face, and dental features more closely resembled other Paleoamerican skeletons, consistent with a shared source population for Native American and Paleoamerican groups.

"The findings … provide no evidence for an early migration to the Americas from southeast Asia or Europe," co-author Deborah Bolnick, an anthropology researcher at the University of Texas, Austin, said in a statement.

"Rather, Paleoamericans — even those with the distinctive skull and facial features — could have come from Siberia too," Bolnick added, noting that "differences between Paleoamericans and Native Americans today are more likely due to evolutionary changes that occurred in Beringia and the Americas over the last 9,000 years."