Clinical OMICS

MAY-JUN 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com May/June 2018 Clinical OMICs 35 The researchers then tested each of the clusters for an association with increased or decreased mRNA levels of target genes. This led to the identifi- cation of 193 somatic expression quan- titative trait loci (eQTLs). Somatic eQTLs are defined here as noncoding loci in which mutations affect target gene expression. The complete anal- ysis yielded a "cancer transcriptional network of 206 regulatory interac- tions between 193 somatic eQTLs and 196 gene-expression-level changes," as described in the paper. In 820 of the 930 tumors analyzed, at least one locus in this network was somatically mutated, "suggesting that transcrip- tional dysregulation through noncod- ing mutations is a general property of most tumors." The researchers reported that non- coding mutations in somatic eQTLs were linked to changes in expression levels of 13 known tumor suppressor genes or oncogenes. Overall, how- ever, known cancer driver genes were not highly represented in the study findings. "We did not expect a lot of overlap," said Zhang, "because can- cer driver genes are defined by the mutations in their coding regions." Kreisberg agreed: "Oncogenes are often characterized by mutations that lead to gain of function changes, and tumor suppressors are often char- acterized by somatic mutations that lead to loss of function. Therefore, we didn't expected to find a lot of non- coding mutations that would drive those genes up or down, because those genes carry out their cancer-causing functions due to mutations some- where in the protein coding regions of the gene itself." To validate the cancer transcrip- tional network, the researchers searched a second cancer database for the somatic eQTLs. They used the International Cancer Genome Con- sortium (ICGC) database, compar- ing their data against genome-wide somatic mutations for 3,382 patients. The majority of the somatic eQTLs found in the TCGA database were also recurrently mutated in the ICGC patient genomes. Interestingly, there are 12 somatic eQTLs from the initial TCGA study that were mutated almost exclusively in melanoma. Among these 12, 10 occurred almost only in melanoma in the ICGC data as well. Linking Mutations to Gene Expression to Phenotype The researchers selected three of the target genes in the study for more detailed investigation, and in partic- ular DAAM1. According to Zhang, a key reason they chose DAAM1 is that the somatic eQTL "makes a lot of sense for upregulation of the gene Gene Deletion May Aid Stroke, Spinal Injury Recovery A researchers at the University of Texas Southwestern's O'Donnell Brain Institute have found a genetic trigger that may improve the brain's ability to heal from a range of debilitating conditions, from strokes to concussions and spinal cord injuries. Their research shows that turning on a gene inside astrocytes results in a smaller scar and, potentially, more effec- tive recovery from injury. These results have implications for treating several brain conditions through gene therapy targeting astrocytes. "We've known that astrocytes can help the brain and spinal cord recover from injury, but we didn't fully under- stand the trigger that activates these cells," explained co-senior study investi- gator Mark Goldberg, M.D., chairman of neurology and neurotherapeutics at UT Southwestern. "Now we'll be able to look at whether turning on the switch we iden- tified can help in the healing process." In the current study, the research- ers deleted the leucine zipper-bear- ing kinase (LZK) gene in astrocytes of one group of injured mice, which decreased the cells' in- jury response and resulted in a larger wound on the spinal cord. Conversely, the scientists overex- pressed the gene in other injured mice, which stimulated the cells' injury response and resulted in a small- er scar. Overexpressing the gene in uninjured mice also activated the astrocytes, confirming LZK as a trigger for as- trogliosis. n (continued on next page) jcrosemann / Getty Images "This study starts to show that there are probably cancer-relevant mutations in other parts of the genome that we need to start paying attention to." —Jason Kreisberg, Ph.D., University of California, San Diego

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