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Genomics in the Journals: Oct 17, 2013

NEW YORK (GenomeWeb News) – Papers by three independent teams reporting in Nature Genetics describe genetic alterations that occur in bladder cancer tumors.

In one of the studies, a Chinese-led team used a combination of whole-genome, whole-exome, and transcriptome sequencing to characterize samples from individuals with a bladder cancer called transitional cell carcinoma, also known as urothelial carcinoma.

By sequencing the exomes of 99 matched tumor-normal pairs, the researchers unearthed more than 11,200 somatic coding mutations and nearly 100 small insertions and deletions. To that, they added copy number profiles determined by low-coverage whole-genome sequencing on the same samples and RNA sequencing profiles for a few dozen of the tumors.

Along with known bladder cancer contributors, the group detected recurrent mutations in a pair of sister chromatid cohesion and segregation, or SCCS, related genes called ESPL1 and STAG2, as well as a fusion between the SCCS gene TACC3 and FGFR3.

"Overall, 32 of the 99 tumors … harbored genetic alterations in the SCCS process," the study's authors wrote. "Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer."

The STAG2 gene was flagged as a prominent player in urothelial bladder cancer in another Nature Genetics study, too. Researchers from Spain and the US performed exome sequencing on samples from 17 individuals with UBC. Together with follow-up screening in another 60 UBC patients, they detected mutations in STAG2 and several other genes involved in cell division, DNA repair, and chromatin function.

In that study, investigators also saw ties between STAG2 loss and better-than-usual bladder cancer survival. Unexpectedly though, particularly given the gene's role in SCCS, they did not see aneuploidy in cells lacking STAG2 expression, hinting that the gene may have an independent tumor suppressor function in bladder cancer.

Likewise, members of an international team led by investigators at Georgetown University that specifically searched for STAG2 mutations in a set of more than 2,200 human cancers found that mutations in the gene are linked to relatively low risk of recurrence in those with bladder cancer.

Authors of that analysis found mutations that abbreviated STAG2 in more than one-third of the papillary non-invasive urothelial carcinoma and some 16 percent of the invasive urothelial carcinoma bladder cancers that they tested.

The concentrations of 13 proteins that circulate in the blood can help in distinguishing between benign and malignant lung nodules, according to a Science Translational Medicine study.

An American and Canadian team led by investigators at the Seattle molecular diagnostics firm Integrated Diagnostics started by using a systems biology approach to narrow in on 371 candidate protein markers that they subsequently screened for in individuals' blood samples using a multiple reaction monitoring, or MRM, mass spectrometry assay.

When the researchers applied these MRM assays — together with bioinformatic analysis — to blood samples from 143 individuals diagnosed with benign lung nodules or early stage lung cancers, they tracked down differences in the levels of 13 proteins that coincided with the presence or absence of lung cancer.

That 13-protein classifier proved useful for distinguishing between individuals with benign or cancerous lung nodules in follow-up experiments, too. In samples from 52 individuals with lung cancer and as many individuals with non-cancerous lung nodules, the team found that the blood-based proteomic profile made it possible to correctly classified benign nodules around 90 percent of the time.

"Physicians often find managing their patient's lung nodules problematic because of the difficulty of differentiating which nodules have a lower or higher probability of lung cancer," co-author Kenneth Fang, Integrated Diagnostics' chief medical officer, said in a statement.

"Given the relative frequency with which physicians use invasive procedures like biopsy and surgery — and their associated risks — there is a high unmet need for a non-invasive test that provides clinicians with an additional, objective parameter for assessing lung nodules."

A new Science study demonstrated the feasibility of producing organisms with "recoded" genomes. Harvard University's George Church, Yale University researcher Farren Isaacs, and colleagues took a crack at constructing a bacterial genome with triplet codon capabilities not normally used in nature.

With the help of multiplex genome editing, the team replaced more than 300 UAG stop codons in the Escherichia coli genome with UAA stop codons before reassigning the function of the original UAG codon — namely the amino acids it's capable of recognizing during translation.

The resulting bugs had altered translational capabilities profiles and an enhanced ability to use non-standard amino acids. Such results hint at the possibility of expanding organisms' repertoire of protein products even further, the study authors said.

Moreover, they noted that the process of genomically recoding the organism made it more resistant to a bacteria-infecting virus called T7, "demonstrating that new genetic codes could enable increased viral resistance."

In an accompanying study, members of the same team took the genomic rearrangement analysis a step further in E. coli to explore the extent to which genomic recoding is possible and the factors that may confound it.

For that study, researchers targeted 13 codons in 42 essential E. coli genes, attempting to remove the relatively rare codons from the highly expressed genes and replace them with alternative codons. Recoding was successful for 26 of the genes, they reported, producing proteins that were more or less the same as those encoded by the original genes though the fitness of recoded strains tended to decline.

"Our results suggest that the genome-wide removal of 13 codons is feasible," Church and his colleagues wrote. "[H]owever, several genome design constraints were apparent, underscoring the importance of a strategy that rapidly prototypes and tests many designs in small pieces."