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101.
Akash Kumar Evan A Boyle Mari Tokita Andrei M Mikheev Michelle C Sanger Emily Girard John R Silber Luis F Gonzalez-Cuyar Joseph B Hiatt Andrew Adey Choli Lee Jacob O Kitzman Donald E Born Daniel L Silbergeld James M Olson Robert C Rostomily Jay Shendure 《Genome biology》2014,15(12)
Background
The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes to assay both point mutations and gene amplifications within spatially distinct regions of 14 glial tumors.Results
We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs). Immunohistochemistry confirms heterogeneity of TP53 mutation and PDGFRA amplification. In all, 3 out of 14 glial tumors surveyed have evidence for heterogeneity for clinically relevant mutations.Conclusions
Our results underscore the need to sample multiple regions in GBM and other glial tumors when devising personalized treatments based on genomic information, and furthermore demonstrate the importance of measuring both point mutation and copy number alteration while investigating genetic heterogeneity within cancer samples.Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0530-z) contains supplementary material, which is available to authorized users. 相似文献102.
NC Elde SJ Child MT Eickbush JO Kitzman KS Rogers J Shendure AP Geballe HS Malik 《Cell》2012,150(4):831-841
In contrast to RNA viruses, double-stranded DNA viruses have low mutation rates yet must still adapt rapidly in response to changing host defenses. To determine mechanisms of adaptation, we subjected the model poxvirus vaccinia to serial propagation in human cells, where its antihost factor K3L is maladapted against the antiviral protein kinase R (PKR). Viruses rapidly acquired higher fitness via recurrent K3L gene amplifications, incurring up to 7%-10% increases in genome size. These transient gene expansions were necessary and sufficient to counteract human PKR and facilitated the gain of an adaptive amino acid substitution in K3L that also defeats PKR. Subsequent reductions in gene amplifications offset the costs associated with larger genome size while retaining adaptive substitutions. Our discovery of viral "gene-accordions" explains how poxviruses can rapidly adapt to defeat different host defenses despite low mutation rates and reveals how classical Red Queen conflicts can progress through unrecognized intermediates. PAPERFLICK: 相似文献
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