Discussion The epidermal growth factor receptor family is of tremen dous biological and clinical importance for many solid epithelial tumors
Careful inspection of these genes reveals some that may have relevance to acute lymphoblastic leukemia, and so drugs for thorough which these are targets provide potential can didates for repurposing. For example, chromosomal aberrations in FGFR1 are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. www.selleckchem.com/products/dorsomorphin-2hcl.html FGFR1 is the drug target of Palifer min, a recombinant human keratinocyte growth factor for the treatment of oral mucositis associated with chemotherapy and radiation therapy. Its also the target for several experimental selleck chemicals llc drugs. A second potential repurposing target for acute lym phoblastic leukemia is the oncogene RET. Previous stu dies found differential expression of RET in acute myeloid leukemia, a distinct but related leukemia. In the version of Drugbank used in this analysis, there is no drug targeting RET for the treatment of ALL. Recently, however, the drug Ponatinib has been approved by the FDA for treatment of Philadelphia chromosome positive acute lymphoblastic leukemia resistant or intolerant to prior tyrosine kinase inhibitor therapy. Thus, one of the high scoring ALL potential drug targets has now been approved for use for use with a new drug. Methods Connecting GWAS reported genes with drug targets using drug indication information from Drugbank GWAS reported genes The GWAS catalog was down loaded from. txt in January 2012. Non disease traits were removed by hand and multiple studies for each disease were com bined into unique sets. Reported genes were extracted to provide the list of GWAS genes for each disease. Drug targets Drugbank data were downloaded from in January 2012. Drugs for each disease in the GWAS list were identified by searching the indication information for all drugs in Drugbank. Then for each of these drugs, we extract all of the corresponding target genes. Verified drug targets Drug targets with the entry Pharmacological action labeled as Yes in the Drugbank. All 4013 GWAS reported genes and 1463 drug targets were mapped to NCBI gene IDs to provide unique identi fiers for comparison.
For the 88 GWAS diseases with drugs in Drugbank, there are 1914 GWAS reported genes and 821 drug targets. The verified drug target set has 353 genes for 81 diseases. For each disease, we compare the list of GWAS reported genes and drug targets and find the overlap between these two lists. Calculating expected overlap between GWAS reported genes and drug targets using a random model We assume there are 20,000 human genes. For a specific disease, if there are m GWAS reported genes, and there are n drug targets for this disease the expected random overlap between the two gene lists for that disease is n m20000. We calculated the expected overlap for each disease and summed these to get the expected total number of overlaps between drug targets and GWAS reported genes for the same disease. SNP impact analysis for GWAS genes and drug target genes 1000 genomes VCF data were downloaded from The 2010 November data set is used. We extracted all non synonymous variants from 1000 genomes data based on Refseq annotation downloaded from the UCSC genome browser in Jan 2012, and calculated the allele frequency for each of the non reference variants by dividing the number of alleles by the number of total possible.