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Fox, Edward Alvin

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Fox

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Edward Alvin

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Fox, Edward Alvin
Author's Publications: search.filters.isAuthorOfPublication.d1153740-82f9-475c-bf83-2c1f8f6eb11e

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Now showing 1 - 6 of 6
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    Next-Generation cDNA Screening for Oncogene and Resistance Phenotypes
    (Public Library of Science, 2012) Shindoh, Nobuaki; Weigert, Oliver; Bird, Liat; Yoda, Akinori; Yoda, Yuka; Sullivan, Timothy J.; Lane, Andrew; Kopp, Nadja; Rodig, Scott; Fox, Edward Alvin; Weinstock, David
    There is a pressing need for methods to define the functional relevance of genetic alterations identified by next-generation sequencing of cancer specimens. We developed new approaches to efficiently construct full-length cDNA libraries from small amounts of total RNA, screen for transforming and resistance phenotypes, and deconvolute by next-generation sequencing. Using this platform, we screened a panel of cDNA libraries from primary specimens and cell lines in cytokine-dependent murine Ba/F3 cells. We demonstrate that cDNA library-based screening can efficiently identify DNA and RNA alterations that confer either cytokine-independent proliferation or resistance to targeted inhibitors, including RNA alterations and intergenic fusions. Using barcoded next-generation sequencing, we simultaneously deconvoluted cytokine-independent clones recovered after transduction of 21 cDNA libraries. This approach identified multiple gain-of-function alleles, including KRAS G12D, NRAS Q61K and an activating splice variant of ERBB2. This approach has broad applicability for identifying transcripts that confer proliferation, resistance and other phenotypes in vitro and potentially in vivo.
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    Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays
    (Public Library of Science, 2007) Attiyeh, Edward F.; Moreau, Lisa A.; Fortina, Paolo; Maris, John M.; George, Rani; Li, Shuli; Neuberg, Donna; Li, Cheng; Fox, Edward Alvin; Meyerson, Matthew; Diller, Lisa; Look, A.
    Background: Neuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP) array. Findings: Multiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%). Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016). Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95%) and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case. Conclusions: This analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy.
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    Genetic Fixity in the Human Major Histocompatibility Complex and Block Size Diversity in the Class I Region Including HLA-E
    (BioMed Central, 2007) Romero, Viviana; Romero, Tatiana; Clavijo, Olga P; Fici, Dolores A; Alford, Dennis R; Awdeh, Zuheir L; Zuñiga, Joaquin; El-Dahdah, Lama; Larsen, Charles; Duke-Cohan, Jonathan; Fox, Edward Alvin; Husain, Zaheed; Almeciga, Ingrid; Alper, Chester; Yunis, Edmond
    Background: The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association. Results: Here, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points both upstream and downstream of HLA-E contributing to alternative block structures within previously identified haplotypes. Through single nucleotide polymorphism (SNP) analysis of the MHC region, we also confirmed the essential genetic fixity, previously inferred by MHC allele analysis, of three conserved extended haplotypes (CEHs), and we demonstrated that commercially-available SNP analysis can be used in the MHC to help define CEHs and CEH fragments. Conclusion: We conclude that to generate high-resolution maps for relating MHC haplotypes to disease susceptibility, both SNP and MHC allele analysis must be conducted as complementary techniques.
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    Exon expression profiling reveals stimulus-mediated exon use in neural cells
    (BioMed Central, 2007) McKee, Adrienne E; Neretti, Nicola; Carvalho, Luis E; Brodsky, Alexander S; Meyer, Clifford; Fox, Edward Alvin; Silver, Pamela
    Background: Neuronal cells respond to changes in intracellular calcium ([Ca2+]i) by affecting both the abundance and architecture of specific mRNAs. Although calcium-induced transcription and transcript variation have both been recognized as important sources of gene regulation, the interplay between these two phenomena has not been evaluated on a genome-wide scale. Results: Here, we show that exon-centric microarrays can be used to resolve the [Ca2+]imodulated gene expression response into transcript-level and exon-level regulation. Global assessments of affected transcripts reveal modulation within distinct functional gene categories. We find that transcripts containing calcium-modulated exons exhibit enrichment for calcium ion binding, calmodulin binding, plasma membrane associated, and metabolic proteins. Additionally, we uncover instances of regulated exon use in potassium channels, neuroendocrine secretory proteins and metabolic enzymes, and demonstrate that regulated changes in exon expression give rise to distinct transcript variants. Conclusion: Our findings connect extracellular stimuli to specific exon behavior, and suggest that changes in transcript and exon abundance are reflective of a coordinated gene expression response to elevated [Ca2+]i. The technology we describe here lends itself readily to the resolution of stimulus-induced gene expression at both the transcript and exon levels.
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    Genomic mapping of RNA polymerase II reveals sites of co-transcriptional regulation in human cells
    (BioMed Central, 2005) Brodsky, Alexander S; Meyer, Clifford; Swinburne, Ian; Hall, Giles; Keenan, Benjamin J; Liu, Xiaole; Fox, Edward Alvin; Silver, Pamela
    Background: Transcription by RNA polymerase II is regulated at many steps including initiation, promoter release, elongation and termination. Accumulation of RNA polymerase II at particular locations across genes can be indicative of sites of regulation. RNA polymerase II is thought to accumulate at the promoter and at sites of co-transcriptional alternative splicing where the rate of RNA synthesis slows. Results: To further understand transcriptional regulation at a global level, we determined the distribution of RNA polymerase II within regions of the human genome designated by the ENCODE project. Hypophosphorylated RNA polymerase II localizes almost exclusively to 5' ends of genes. On the other hand, localization of total RNA polymerase II reveals a variety of distinct landscapes across many genes with 74% of the observed enriched locations at exons. RNA polymerase II accumulates at many annotated constitutively spliced exons, but is biased for alternatively spliced exons. Finally, RNA polymerase II is also observed at locations not in gene regions. Conclusion: Localizing RNA polymerase II across many millions of base pairs in the human genome identifies novel sites of transcription and provides insights into the regulation of transcription elongation. These data indicate that RNA polymerase II accumulates most often at exons during transcription. Thus, a major factor of transcription elongation control in mammalian cells is the coordination of transcription and pre-mRNA processing to define exons.
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    Inferring Loss-of-Heterozygosity from Unpaired Tumors Using High-Density Oligonucleotide SNP Arrays
    (Public Library of Science, 2006) Park, Yuhyun; Hao, Ke; Zhao, Xiaojun; Mellinghoff, Ingo K; Hofer, Matthias D; Descazeaud, Aurelien; Rubin, Mark A; Sellers, William R; Bourne, Philip; Beroukhim, Rameen; Lin, Ming; Garraway, Levi; Fox, Edward Alvin; Hochberg, Ephraim; Meyerson, Matthew; Wong, Wing H; Li, Cheng
    Loss of heterozygosity (LOH) of chromosomal regions bearing tumor suppressors is a key event in the evolution of epithelial and mesenchymal tumors. Identification of these regions usually relies on genotyping tumor and counterpart normal DNA and noting regions where heterozygous alleles in the normal DNA become homozygous in the tumor. However, paired normal samples for tumors and cell lines are often not available. With the advent of oligonucleotide arrays that simultaneously assay thousands of single-nucleotide polymorphism (SNP) markers, genotyping can now be done at high enough resolution to allow identification of LOH events by the absence of heterozygous loci, without comparison to normal controls. Here we describe a hidden Markov model-based method to identify LOH from unpaired tumor samples, taking into account SNP intermarker distances, SNP-specific heterozygosity rates, and the haplotype structure of the human genome. When we applied the method to data genotyped on 100 K arrays, we correctly identified 99% of SNP markers as either retention or loss. We also correctly identified 81% of the regions of LOH, including 98% of regions greater than 3 megabases. By integrating copy number analysis into the method, we were able to distinguish LOH from allelic imbalance. Application of this method to data from a set of prostate samples without paired normals identified known regions of prevalent LOH. We have developed a method for analyzing high-density oligonucleotide SNP array data to accurately identify of regions of LOH and retention in tumors without the need for paired normal samples.