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This Week in PNAS: Feb 19, 2013

A Memorial Sloan-Kettering Cancer Center-led team presents a model for doing integrated analyses of cancer genomes in a study slated to appear online this week in the Proceedings of the National Academy of Sciences. Using data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas, the researchers demonstrated that their statistical framework — called iCluster+ — accurately classified hundreds of cancer cell lines by sites of origin, subgroup, and so on. In the process, the study's authors explain, the iCluster+ analyses uncovered new drug sensitivity patterns and cancer sub-types, including a newly described colorectal cancer sub-type with lower-than-usual levels of TP53 gene mutation or chromosomal instability.

The University of Texas MD Anderson Cancer Center's Wenyi Wang and colleagues describe family-based variant-calling software designed to find rare Mendelian variants contributing to disease. Along with simulation experiments, the group applied its Family-Based Sequencing — or FamSeq — analytical approach to search for rare variants in whole-genome and targeted sequencing data on 92 samples from 28 families affected by neurodevelopmental disorders or Wilms tumor. By bringing together raw sequencing reads and Mendelian disease transmission patterns, they say, the method makes it possible to see rare variants with potential ties to disease genes while weeding out false-positive de novo variants. For their new analysis, the study's authors also went on to explore factors affecting the extent to which FamSeq improved such variant calls.

An international team led by investigators at Johns Hopkins University School of Medicine report on findings from an RNA interference-based functional genomic screen for kinase enzymes related to retinal ganglion cell survival. The researchers targeted 623 kinase-coding genes in primary mouse retinal ganglion cells using a set of nearly 1,900 small interfering RNAs. The screen unearthed a dual leucine zipper kinase encoded by the DLK gene, while follow-up experiments delineated details of DLK's role in retinal ganglion cell death. Using a rodent model of optic neuropathy, the investigators also identified a small molecule called tozasertib that curbs DLK-mediated retinal ganglion cell death.