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Weir, Barbara Ann

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Weir

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Barbara Ann

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Weir, Barbara Ann
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    Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
    (eLife Sciences Publications, Ltd, 2017) Paolella, Brenton R.; Gibson, William; Urbanski, Laura M; Alberta, John; Zack, Travis Ian; Bandopadhayay, Pratiti; Nichols, Caitlin; Agarwalla, Pankaj Kumar; Brown, Meredith S; Lamothe, Rebecca; Yu, Yong; Choi, Peter; Obeng, Esther A; Heckl, Dirk; Wei, Guo; Wang, Belinda; Tsherniak, Aviad; Vazquez, Francisca; Weir, Barbara Ann; Root, David E; Cowley, Glenn S; Buhrlage, Sara; Stiles, Charles; Ebert, Benjamin; Hahn, William; Reed, Robin; Beroukhim, Rameen
    Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency. DOI: http://dx.doi.org/10.7554/eLife.23268.001
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    Absolute quantification of somatic DNA alterations in human cancer
    (2015) Carter, Scott L.; Cibulskis, Kristian; Helman, Elena; McKenna, Aaron; Shen, Hui; Zack, Travis Ian; Laird, Peter W.; Onofrio, Robert C.; Winckler, Wendy; Weir, Barbara Ann; Beroukhim, Rameen; Pellman, David; Levine, Douglas A.; Lander, Eric; Meyerson, Matthew; Getz, Gad
    We developed a computational method (ABSOLUTE) that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. ABSOLUTE can detect subclonal heterogeneity, somatic homozygosity, and calculate statistical sensitivity to detect specific aberrations. We used ABSOLUTE to analyze ovarian cancer data and identified pervasive subclonal somatic point mutations. In contrast, mutations occurring in key tumor suppressor genes, TP53 and NF1 were predominantly clonal and homozygous, as were mutations in a candidate tumor suppressor gene, CDK12. Analysis of absolute allelic copy-number profiles from 3,155 cancer specimens revealed that genome-doubling events are common in human cancer, and likely occur in already aneuploid cells. By correlating genome-doubling status with mutation data, we found that homozygous mutations in NF1 occurred predominantly in non-doubled samples. This finding suggests that genome doubling influences the pathways of tumor progression, with recessive inactivation being less common after genome doubling.
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    Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies
    (Nature Publishing Group, 2014) Cowley, Glenn S; Weir, Barbara Ann; Vazquez, Francisca; Tamayo, Pablo; Scott, Justine A; Rusin, Scott; East-Seletsky, Alexandra; Ali, Levi D; Gerath, William FJ; Pantel, Sarah; Lizotte, Patrick H; Jiang, Guozhi; Hsiao, Jessica; Tsherniak, Aviad; Dwinell, Elizabeth; Aoyama, Simon; Okamoto, Michael; Harrington, William; Gelfand, Ellen; Green, Thomas M; Tomko, Mark J; Gopal, Shuba; Wong, Terence C; Li, Hubo; Howell, Sara; Stransky, Nicolas; Liefeld, Ted; Jang, Dongkeun; Bistline, Jonathan; Hill Meyers, Barbara; Armstrong, Scott A; Anderson, Ken C; Stegmaier, Kimberly; Reich, Michael; Pellman, David; Boehm, Jesse S; Mesirov, Jill P; Golub, Todd; Root, David E; Hahn, William
    Using a genome-scale, lentivirally delivered shRNA library, we performed massively parallel pooled shRNA screens in 216 cancer cell lines to identify genes that are required for cell proliferation and/or viability. Cell line dependencies on 11,000 genes were interrogated by 5 shRNAs per gene. The proliferation effect of each shRNA in each cell line was assessed by transducing a population of 11M cells with one shRNA-virus per cell and determining the relative enrichment or depletion of each of the 54,000 shRNAs after 16 population doublings using Next Generation Sequencing. All the cell lines were screened using standardized conditions to best assess differential genetic dependencies across cell lines. When combined with genomic characterization of these cell lines, this dataset facilitates the linkage of genetic dependencies with specific cellular contexts (e.g., gene mutations or cell lineage). To enable such comparisons, we developed and provided a bioinformatics tool to identify linear and nonlinear correlations between these features.
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    SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas
    (Springer Nature, 2009) Bass, Adam; Watanabe, Hideo; Mermel, Craig; Yu, Soyoung; Perner, Sven; Verhaak, Roel; Kim, So Jeong; Wardwell, Leslie; Tamayo, Pablo; Gat-Viks, Irit; Ramos, Alex H; Woo, Michele S; Weir, Barbara Ann; Getz, Gad; Beroukhim, Rameen; O, Michael; Dutt, Amit; Rozenblatt-Rosen, Orit; Dziunycz, Piotr; Komisarof, Justin; Chirieac, Lucian; LaFargue, Christopher J; Scheble, Veit; Wilbertz, Theresia; Ma, Changqing; Rao, Shilpa; Nakagawa, Hiroshi; Stairs, Douglas B; Lin, Lin; Giordano, Thomas J; Wagner, Patrick; Minna, John D; Gazdar, Adi F; Zhu, Chang Qi; Brose, Marcia S; Cecconello, Ivan; Jr, Ulysses Ribeiro; Marie, Suely K; Dahl, Olav; Shivdasani, Ramesh; Tsao, Ming-Sound; Rubin, Mark A; Wong, Kwok-Kin; Regev, Aviv; Hahn, William; Beer, David G; Rustgi, Anil K; Meyerson, Matthew
    Lineage survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development.1,2 Here we show that a peak of genomic amplification on chromosome 3q26.33, found in squamous cell carcinomas (SCCs) of the lung and esophagus, contains the transcription factor gene SOX2—which is mutated in hereditary human esophageal malformations3 and necessary for normal esophageal squamous development4, promotes differentiation and proliferation of basal tracheal cells5 and co-operates in induction of pluripotent stem cells.6,7,8 SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These observations identify SOX2 as a novel lineage survival oncogene in lung and esophageal SCC.
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    An integrative analysis reveals functional targets of GATA6 transcriptional regulation in gastric cancer
    (Springer Nature, 2013) Sulahian, R; Casey, F; Shen, J; Qian, Zhirong; Shin, H; Ogino, Shuji; Weir, Barbara Ann; Vazquez, F; Liu, Xiaole; Hahn, William; Bass, Adam; Chan, Vivian; Shivdasani, Ramesh
    Lineage-restricted transcription factors (TFs) are frequently mutated or overexpressed in cancer and contribute toward malignant behaviors, but the molecular bases of their oncogenic properties are largely unknown. Because TF activities are difficult to inhibit directly with small molecules, the genes and pathways they regulate might represent more tractable targets for drug therapy. We studied GATA6, a TF gene that is frequently amplified or overexpressed in gastric, esophageal, and pancreatic adenocarcinomas. GATA6-overexpressing gastric cancer cell lines cluster in gene expression space, separate from non-overexpressing lines. This expression clustering signifies a shared pathogenic group of genes that GATA6 may regulate through direct cis-element binding. We used chromatin immunoprecipation and sequencing (ChIP-seq) to identify GATA6-bound genes and considered TF occupancy in relation to genes that respond to GATA6 depletion in cell lines and track with GATA6 mRNA (synexpression groups) in primary gastric cancers. Among other cellular functions, GATA6-occupied genes control apoptosis and govern M-phase of the cell cycle. Depletion of GATA6 reduced levels of the latter transcripts and arrested cells in G2 and M phases of the cell cycle. Synexpression in human tumor samples identified likely direct transcriptional targets substantially better than consideration only of transcripts that respond to GATA6 loss in cultured cells. Candidate target genes responded to loss of GATA6 or its homolog GATA4 and even more to depletion of both proteins. Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed, and GATA6-bound genes encode TFs such as MYC, HES1, RARB, and CDX2. Thus, many downstream effects occur indirectly through other TFs and GATA6 activity in gastric cancer is partially redundant with GATA4. This integrative analysis of locus occupancy, gene dependency, and synexpression provides a functional signature of GATA6-overexpressing gastric cancers, revealing both limits and new therapeutic directions for a challenging and frequently fatal disease.
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    PAK1 is a Breast Cancer Oncogene that Coordinately Activates MAPK and MET Signaling
    (Nature Publishing Group, 2012) Shrestha, Yashaswi; Schafer, Eric J.; Boehm, Jesse S.; He, Frank; Wang, Shumei; Barretina, Jordi; Thomas, Sapana Rachael; Du, Jinyan; Weir, Barbara Ann; Zhao, Jean; Golub, Todd; Beroukhim, Rameen; Hahn, William; Polyak, Kornelia
    Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK Mitogen-Activated Protein Kinase (MAPK) pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified PAK1 as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of Merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.
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    Major Copy Proportion Analysis of Tumor Samples Using SNP Arrays
    (BioMed Central, 2008) Li, Cheng; Beroukhim, Rameen; Weir, Barbara Ann; Winckler, Wendy; Garraway, Levi; Sellers, William R; Meyerson, Matthew
    Background: Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the human genome and are useful as genomic markers. Oligonucleotide SNP microarrays have been developed for high-throughput genotyping of up to 900,000 human SNPs and have been used widely in linkage and cancer genomics studies. We have previously used Hidden Markov Models (HMM) to analyze SNP array data for inferring copy numbers and loss-of-heterozygosity (LOH) from paired normal and tumor samples and unpaired tumor samples. Results: We proposed and implemented major copy proportion (MCP) analysis of oligonucleotide SNP array data. A HMM was constructed to infer unobserved MCP states from observed allele-specific signals through emission and transition distributions. We used 10 K, 100 K and 250 K SNP array datasets to compare MCP analysis with LOH and copy number analysis, and showed that MCP performs better than LOH analysis for allelic-imbalanced chromosome regions and normal contaminated samples. The major and minor copy alleles can also be inferred from allelic-imbalanced regions by MCP analysis. Conclusion: MCP extends tumor LOH analysis to allelic imbalance analysis and supplies complementary information to total copy numbers. MCP analysis of mixing normal and tumor samples suggests the utility of MCP analysis of normal-contaminated tumor samples. The described analysis and visualization methods are readily available in the user-friendly dChip software.
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    Allele-Specific Amplification in Cancer Revealed by SNP Array Analysis
    (Public Library of Science, 2005) LaFramboise, Thomas; Weir, Barbara Ann; Zhao, Xiaojun; Beroukhim, Rameen; Li, Cheng; Harrington, David; Sellers, William R; Meyerson, Matthew
    Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ.