NEW YORK (GenomeWeb) – In Nature Genetics, researchers from the Memorial Sloan Kettering Cancer Center and the University of Copenhagen described some of the common non-protein-coding mutations they detected in data for hundreds of cancer genomes.
Using genome sequences generated for 863 human tumor samples for the Cancer Genome Atlas and other cancer sequencing efforts, the team came up with a genome-wide catalog representing recurrent, cancer-related mutations in non-protein-coding regions of the genome.
During their search for somatic mutations with possible regulatory roles, for example, the researchers detected recurrent alterations in the promoter regions of genes such as TERT, PLEKHS1, WDR74, and SDHD in several cancer types — patterns they explored further in follow-up analyses that included a few dozen tumors for which exome sequences and gene expression profiles were available.
"The non-protein-coding cancer genome remains widely unexplored," corresponding author William Lee, a computational biology and radiation oncology researcher at MSKCC, and his colleagues wrote, "and our findings represent a step toward targeting the entire genome for clinical purposes."
A Nature Medicine study by investigators in the US, China, and Canada considered the metabolic features associated with a form of pancreatic cancer called pancreatic ductal adenocarcinoma (PDAC).
The team did liquid chromatography-tandem mass spectrometry-based metabolite testing on blood samples from more than 450 pancreatic cancer cases and around 900 unaffected controls who had been enrolled as part of four different prospective cohorts. All of the individuals were cancer-free when their respective studies began and followed for two years or longer. On average, pancreatic cancer patients developed the disease almost nine years after their first blood samples were drawn.
When researchers looked at blood metabolite patterns in these individuals, they identified 15 metabolites that were present at different levels in the blood of those who went on to develop pancreatic cancer compared to those who didn't.
That set included three branched-chain amino acids — isoleucine, leucine, and valine — that were found at significantly higher levels in individuals with PDAC, especially in the two to five years prior to their disease diagnosis. Follow-up experiments indicated that this effect was a consequence of muscle breakdown in the individuals, suggesting such events can occur quite some time before pancreatic tumors are generally detected.
"What was surprising about our results was that it appears the breakdown of muscle protein begins much earlier in the disease process than previously appreciated," co-senior author Matthew Vander Heiden, a researcher affiliated with the Dana-Farber Cancer Institute and the Massachusetts Institute of Technology, said in a statement, noting that the study "has the potential to spur progress in detecting pancreatic tumors earlier and identifying new treatment strategies for those with the disease."
In one of two biofuel-related papers appearing in Science this week, researchers from Sweden and Denmark used genome sequencing, array-based gene expression profiling, and metabolic flux patterns to look at the shifts required to produce Saccharomyces cerevisiae yeast capable of growing and producing ethanol at the sorts of elevated temperatures used to perform other steps in the biofuel production process such as feedstock breakdown.
Through a series of adaptive laboratory evolution experiments, the team selected for yeast strains that were better able to grow and produce ethanol by fermentation at temperatures beyond 40 degrees Celsius (about 104 degrees Fahrenheit).
When they did genome sequencing and transcriptional analyses on seven such strains grown at just over 40 degrees Celsius, the researchers detected a few dozen single nucleotide changes affecting 18 yeast genes, particularly those genes coding for proteins involved in membrane structure, DNA repair, and DNA replication.
Most of the strains harbored relatively large duplications, they noted, including chromosome III changes that affected yeast DNA damage- and respiration-related genes. All seven strains, which were produced from three source populations, contained nonsense mutations affecting a gene that codes for the so-called C-5 sterol desaturase enzyme.
The latter change appeared to alter the sterols that the temperature-tolerant yeast produced, the study's authors found, shifting the production of a sterol called ergosterol over to production of an alternative form known as fecosterol, in tandem with a rise in the expression of genes contributing to sterol production.
"Since that mutation took place in three independent cultivations, it appears to be the most important factor in terms of the yeast becoming thermotolerant," corresponding author Jens Nielsen, a systems biology researcher with Chalmers University of Technology's Novo Nordisk Foundation Center for Biosustainability, said in a statement. "This shows how rapidly evolution can change an organism."
"It is interesting that the structure in fecosterol is the same as in sterol-like molecules," he added, "which protect some bacteria and plants against high temperatures."
For another Science study, a University of Oxford- and University of Leuven-led team took a look at early transmission events that led to the ongoing epidemic of HIV-1, group M infections in humans.
Through statistical analyses of HIV-1 sequences from isolates collected in central Africa, the researchers put the earliest group M infections in humans back to roughly the 1920s in Kinshasa, the capital of the Democratic Republic of the Congo.
Although HIV viruses have made the jump to humans more than a dozen times, including transmission of HIV-1 from groups O, N, and P, authors of the analysis explained, the group M form of the disease is thus far the only one that has spread to pandemic proportions.
The team retraced this spread out of Kinshasa to other parts of Africa and beyond over time using genetic models designed to follow viral lineage migration. The analysis suggests group M HIV-1 movement was aided by factors such as the establishment of an active railway system, urban growth, and other social changes.
"'For the first time we have analyzed all the available evidence using the latest phylogeographic techniques, which enable us to statistically estimate where a virus comes from," University of Oxford zoology researcher Oliver Pybus, a co-corresponding author on the study, said in a statement.
"It seems a combination of factors in Kinshasa in the early 20th Century created a 'perfect storm' for the emergence of HIV," Pybus said, "leading to a generalised epidemic with unstoppable momentum that unrolled across sub-Saharan Africa."