Showing papers by "Pablo Tamayo published in 2011"
TL;DR: A new version of the database, MSigDB 3.0, is reported, with over 6700 gene sets, a complete revision of the collection of canonical pathways and experimental signatures from publications, enhanced annotations and upgrades to the web site.
Abstract: Motivation: Well-annotated gene sets representing the universe of the biological processes are critical for meaningful and insightful interpretation of large-scale genomic data. The Molecular Signatures Database (MSigDB) is one of the most widely used repositories of such sets.
Results: We report the availability of a new version of the database, MSigDB 3.0, with over 6700 gene sets, a complete revision of the collection of canonical pathways and experimental signatures from publications, enhanced annotations and upgrades to the web site.
Availability and Implementation: MSigDB is freely available for non-commercial use at http://www.broadinstitute.org/msigdb.
Contact: gsea@broadinstitute.org
4,128 citations
TL;DR: It is shown that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals.
Abstract: Purpose Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. Patients and Methods We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization–based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets. Results Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical ...
629 citations
TL;DR: Assessment of the essentiality of 11,194 genes in 102 human cancer cell lines shows that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.
Abstract: A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overexpressed in ovarian cancer cell lines. One such gene, PAX8, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.
422 citations
TL;DR: It is shown how integration of high-level clinical and genomic features or risk factors, including disease subtype, can yield more comprehensive, accurate, and biologically interpretable prediction models for relapse versus no-relapse classification.
Abstract: Purpose Despite significant progress in the molecular understanding of medulloblastoma, stratification of risk in patients remains a challenge. Focus has shifted from clinical parameters to molecular markers, such as expression of specific genes and selected genomic abnormalities, to improve accuracy of treatment outcome prediction. Here, we show how integration of high-level clinical and genomic features or risk factors, including disease subtype, can yield more comprehensive, accurate, and biologically interpretable prediction models for relapse versus no-relapse classification. We also introduce a novel Bayesian nomogram indicating the amount of evidence that each feature contributes on a patient-by-patient basis. Patients and Methods A Bayesian cumulative log-odds model of outcome was developed from a training cohort of 96 children treated for medulloblastoma, starting with the evidence provided by clinical features of metastasis and histology (model A) and incrementally adding the evidence from gene-...
77 citations
TL;DR: This argument criticizes GSEA’s nonparametric nature and use of an empirical null distribution as unnecessary and hard to compute and provides strong empirical evidence that gene-gene correlations cannot be ignored and should be taken into account when estimating enrichment significance.
7 citations
Patent•
30 Nov 20115 citations
TL;DR: The results provide strong empirical evidence that gene-gene correlations cannot be ignored due to the significant variance inflation they produced on the enrichment scores and should be taken into account when estimating gene set enrichment significance.
1 citations
TL;DR: It is demonstrated that aberrant epigenetic silencing of the tumor suppressor gene BIN1 is a conserved event in SNF5-deficient cancers and contributes to tumorigenesis.
Abstract: SNF5 (SMARCB1/INI1/BAF47), a core subunit of SWI/SNF chromatin remodeling complexes, is a potent tumor suppressor that is specifically inactivated in a variety of aggressive pediatric cancers. We have recently demonstrated that SNF5 acts as a tumor suppressor not genetically via maintenance of genome integrity, but epigenetically via transcriptional regulation. However, few of the target genes essential for oncogenesis following SNF5 loss have been identified. Here, we demonstrate that aberrant epigenetic silencing of the tumor suppressor gene BIN1 is a conserved event in SNF5-deficient cancers and contributes to tumorigenesis. Comparative genomewide expression analysis reveals that BIN1 expression is strongly downregulated in SNF5-deficient malignant rhabdoid tumors (MRT) relative to other human tumors, and we also observe decreased Bin1 expression in murine Snf5-deficient lymphomas. The underlying mechanism is epigenetic silencing as reintroduction of SNF5 into deficient tumor cell lines results in increased SWI/SNF recruitment to the BIN1 promoter and increased BIN1 expression. Furthermore, expression of BIN1 specifically compromises the proliferation of SNF5-deficient MRT cell lines. BIN1 encodes a family of alternatively spliced adaptor proteins that have been implicated in cellular differentiation, tumor suppression, and immune escape of transformed cells, but its regulation has not been well characterized. Identification of BIN1 as a key SNF5 target reveals a novel mechanism by which epigenetically based changes can drive cancer formation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 66. doi:10.1158/1538-7445.AM2011-66
1 citations
TL;DR: The expression data confirms that patients whose pre-therapy marrow shows under-expression of the JNK gene set are precisely those who benefit from this drug therapy and those patients who already over-express these genes are unlikely to respond.
1 citations