The vast majority of false positives were due to undetected heter

The vast majority of false positives were due to undetected heterozygous alleles in the germline. Somatic mutations were observed Inhibitors,Modulators,Libraries in two well characterized tumor suppressor genes, TP53 and a truncating mutation in RB1 removing 75% of its coding sequence, with TP53 also within a region of heterozygous loss. Inhibitors,Modulators,Libraries Transcriptome analysis Whole transcriptome shotgun sequencing was conducted to profile the expression of tumor transcripts. In the absence of an equivalent nor mal tissue for comparison, we compared expression changes to the patients leukocytes and a compendium of 50 tumor derived WTSS datasets, which would avoid spurious observations due to technical or methodologi cal differences between gene expression profiling plat forms.

This compendium approach allowed us to identify a specific and unique molecular transcript signa ture for this tumor, as compared to unrelated tumors, enriched in cancer causing events specific to the patients tumor and therefore should represent relevant drug targets for therapeutic intervention. Inhibitors,Modulators,Libraries There were 3,064 differentially expressed genes in the lung tumor versus the blood compendium. This analysis provided insight into those genes whose expression rate was likely to be a driving factor specific to this tumor, not identifying genes that correlate simply with proliferation and cell division. It is conceivable that such an approach, coupled with a greater understanding from multiple tumor datasets, could be replaced by the absolute quan tification of oncogene expression as a means to deter mine clinical relevance.

Changes in Inhibitors,Modulators,Libraries expression in both metastases were significantly associated with copy num ber Inhibitors,Modulators,Libraries changes. A large number of canonical pathways were identified as over represented in the pathway analysis. Specifically, ten pathways were significant from the lung versus blood compendium gene lists, two from skin versus blood com pendium, and 98 from skin versus lung. These included many molecular mechanisms of cancer and cancer related signaling pathways, such as mammalian target of rapamycin signaling, p53 signaling, Myc mediated apoptosis signaling, vascular endothelial growth factor signaling, phosphoinositide 3 kinase AKT signaling, and phosphatase and ten sin homolog signaling, amongst others. We correlated the mutated, amplified or differentially expressed genes with known cancer pathways from the Kyoto Encyclopedia of Genes and Genomes database and to drug targets present in the Drug Bank database.

The 15 amplified, over expressed or mutated genes in cancer pathways targetable by approved drugs are listed in Table S2 in Additional file 1. Some amplified genes, such as NKX3 1, RBBP8 and CABL1, were implicated in cancer but are not well char acterized in this role. In addition, they did not have Pacritinib FLT3 known drugs targeting them.

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