Multi-dimensional cancer genomic data generated by large-scale investigations of tumor genomic alterations such as the The Cancer Genome Atlas Project (TCGA) is expected to greatly facilitate understanding of cancer etiology, identification of novel drug targets and development of personalized treatment based on tumor genomic profiling. Our group has developed analytical tools and has actively participated in the analysis of the integrated genomic data for TCGA. We were the first to identify NF1 as one of the most frequently mutated genes in glioblastoma multiforme (GBM), a finding that was later validated and reported in the TCGA network paper published in Nature (1). Our visualization tools were used by the TCGA network members in identifying core pathways involved in GBM. Recently we discovered and reported to TCGA project leadership extensive loss of heterozygosity and reversion of germline mutations in BRCA1/2 in TCGA ovarian tumors. These findings have been validated by Next-generation sequencing data. We are also collaborating with TCGA project team on preparing a manuscript that gives an update of mutation profile of the significant genes identified in the pilot study. Besides contributing to TCGA, our group has been responsible for analyzing mutations for NCI's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. Recently we identified novel recurrent somatic mutations that were only found in acute lymphoblastic leukemia (ALL) patients with poor clinical outcome (2, 3). These mutations cause constitutive activation of the JAK receptor tyrosine kinase gene, and the availability of chemical inhibitors of this gene suggest that this finding can be translated into a novel therapy for poor outcome ALL patients (2). Phase I clinical trial based on this finding is currently being organized by NCI CTEP and Childrens Oncology Group. We are currently preparing a manuscript that summarizes the major biological pathways affected by somatic mutations and copy number alterations in ALL. We have also identified activating somatic mutations in ALK in TARGET neuroblastoma (NBL) tumors. A clinical trial of ALK inhibition therapy for children with refractory NBL is ongoing under the leadership of TARGET NBL. We have ongoing collaboration with Drs. James Downing and Charles Mulligan at St. Jude Childrens Hospital to compare the somatic mutation changes occurred at diagnosis and those at the relaps to gain insight into biological pathways that involved in failure to treatment. We have developed novel analytical methods for analyzing Next-generation sequencing data focusing on the analysis of fusion protein and insertion/deletions. These events are difficult to be detected by current Next-gen mapping methods. In an analysis of Next-gen data of three ALL samples, we have identified novel insertion/deletions that can disrupt protein function and alternative splicing events that affect 25% of the transcriptome. We will participate in the Next-gen sequencing data analysis of TCGA Ovarian and GBM for the TCGA project when the data is available. Understanding the mechanisms of drug response is critical for developing effective cancer therapy. In collaboration with Drs. Jim Doroshow and Anne Monks, we analyzed the correlation between drug-induced gene expression changes and drug sensitivity in the NCI-60 cell line panel. Expression data were collected from untreated cell lines as well as those treated with low- or high-concentration drug for 2hr, 6hr and 24hr. Drug sensitivity was calculated as GI50 (i.e. 50% growth inhibitory concentration) for each cell line. To date, we have analyzed data collected from doxorubicin, bortezomib, taxol, dasatinib, and sunitinib. Each drug is unique in the onset of massive cellular transcription change, response to low versus high treatment and affected biological pathways. For doxorubicin, we identified that the dual contribution of MDR-1 and activation of the p53 pathway to DOXO-sensitivity, establishing a strong association between the p53 pathway activation with the composite genotype of wild-type p53 mutant p16 across the NCI60 cell line panel. For dasatinib, induction of MYC at 2 hours appear to be a hallmark associated with drug sensitivity. For sunitinib, activation of tyrosine kinase genes involved in cellular growth such as EGFR, STAT and KRAS appear to be associated with drug sensitivity. Experimental validation is ongoing to evaluate the candidate genes identified by our analysis.
| Edmonson, Michael N; Zhang, Jinghui; Yan, Chunhua et al. (2011) Bambino: a variant detector and alignment viewer for next-generation sequencing data in the SAM/BAM format. Bioinformatics 27:865-6 |
| Greenblum, Sharon I; Efroni, Sol; Schaefer, Carl F et al. (2011) The PathOlogist: an automated tool for pathway-centric analysis. BMC Bioinformatics 12:133 |
| Efroni, Sol; Ben-Hamo, Rotem; Edmonson, Michael et al. (2011) Detecting cancer gene networks characterized by recurrent genomic alterations in a population. PLoS One 6:e14437 |
| Clifford, Robert J; Zhang, Jinghui; Meerzaman, Daoud M et al. (2010) Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology 52:2034-43 |
| Mullighan, Charles G; Zhang, Jinghui; Harvey, Richard C et al. (2009) JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 106:9414-8 |
| Mullighan, Charles G; Su, Xiaoping; Zhang, Jinghui et al. (2009) Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 360:470-80 |
| MGC Project Team; Temple, Gary; Gerhard, Daniela S et al. (2009) The completion of the Mammalian Gene Collection (MGC). Genome Res 19:2324-33 |
| Braun, Rosemary; Rowe, William; Schaefer, Carl et al. (2009) Needles in the haystack: identifying individuals present in pooled genomic data. PLoS Genet 5:e1000668 |
| Madhavan, Subha; Zenklusen, Jean-Claude; Kotliarov, Yuri et al. (2009) Rembrandt: helping personalized medicine become a reality through integrative translational research. Mol Cancer Res 7:157-67 |
| Buetow, Kenneth H (2009) An infrastructure for interconnecting research institutions. Drug Discov Today 14:605-10 |
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