Person: Baca, Sylvan
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Baca
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Sylvan
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Baca, Sylvan
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Publication The landscape of somatic mutations in primary prostate adenocarcinoma(2013-10-08) Baca, Sylvan; Garraway, Levi Alexander; Meyerson, Matthew; Wu, Catherine; Monti, Stefano; Park, PeterProstate cancer is the second leading cause of cancer deaths among men. Targeted analyses of DNA from prostate cancers have identified recurrent somatic alterations that promote tumor growth and survival. Only recently, however, has the comprehensive analysis of cancer genomes become possible due to rapid advances in DNA sequencing technology.Publication Unraveling the clonal hierarchy of somatic genomic aberrations(BioMed Central, 2014) Prandi, Davide; Baca, Sylvan; Romanel, Alessandro; Barbieri, Christopher E; Mosquera, Juan-Miguel; Fontugne, Jacqueline; Beltran, Himisha; Sboner, Andrea; Garraway, Levi; Rubin, Mark A; Demichelis, FrancescaDefining the chronology of molecular alterations may identify milestones in carcinogenesis. To unravel the temporal evolution of aberrations from clinical tumors, we developed CLONET, which upon estimation of tumor admixture and ploidy infers the clonal hierarchy of genomic aberrations. Comparative analysis across 100 sequenced genomes from prostate, melanoma, and lung cancers established diverse evolutionary hierarchies, demonstrating the early disruption of tumor-specific pathways. The analyses highlight the diversity of clonal evolution within and across tumor types that might be informative for risk stratification and patient selection for targeted therapies. CLONET addresses heterogeneous clinical samples seen in the setting of precision medicine. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0439-6) contains supplementary material, which is available to authorized users.Publication Erratum to: Unraveling the clonal hierarchy of somatic genomic aberrations(BioMed Central, 2017) Prandi, Davide; Baca, Sylvan; Romanel, Alessandro; Barbieri, Christopher E.; Mosquera, Juan-Miguel; Fontugne, Jacqueline; Beltran, Himisha; Sboner, Andrea; Garraway, Levi; Rubin, Mark A.; Demichelis, FrancescaPublication Gastrointestinal Adenocarcinomas of the Esophagus, Stomach, and Colon Exhibit Distinct Patterns of Genome Instability and Oncogenesis(American Association for Cancer Research (AACR), 2012) Dulak, A. M.; Schumacher, S. E.; van Lieshout, J.; Imamura, Y.; Fox, Cameron; Shim, B.; Ramos, A. H.; Saksena, G.; Baca, Sylvan; Baselga, J.; Tabernero, J.; Barretina, J.; Enzinger, Peter; Corso, G.; Roviello, F.; Lin, Lin; Bandla, S.; Luketich, J. D.; Pennathur, A.; Meyerson, Matthew; Ogino, Shuji; Shivdasani, Ramesh; Beer, Dennis; Godfrey, T. E.; Beroukhim, Rameen; Bass, AdamA more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy. Using data from high-density genomic profiling arrays, we conducted an analysis of somatic copy-number aberrations (SCNAs) in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers. Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors. We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined. Amplified genes were noted in 37% of gastric/esophageal tumors, including in therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting the potential utility of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared to colorectal cancers. Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture. Together, our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions.Publication The Genomic Landscape of Prostate Cancer(Frontiers Research Foundation, 2012) Baca, Sylvan; Garraway, LeviProstate cancer is a common malignancy in men, with a markedly variable clinical course. Somatic alterations in DNA drive the growth of prostate cancers and may underlie the behavior of aggressive versus indolent tumors. The accelerating application of genomic technologies over the last two decades has identified mutations that drive prostate cancer formation, progression, and therapeutic resistance. Here, we discuss exemplary somatic mutations in prostate cancer, and highlight mutated cellular pathways with biological and possible therapeutic importance. Examples include mutated genes involved in androgen signaling, cell cycle regulation, signal transduction, and development. Some genetic alterations may also predict the clinical course of disease or response to therapy, although the molecular heterogeneity of prostate tumors poses challenges to genomic biomarker identification. The widespread application of massively parallel sequencing technology to the analysis of prostate cancer genomes should continue to advance both discovery-oriented and diagnostic avenues.Publication Genetic Determinants of Chromatin Reveal Prostate Cancer Risk Mediated by Context-Dependent Gene Regulation(Cold Spring Harbor Laboratory, 2022-09-07) Baca, Sylvan; Singler, Cassandra; Zacharia, Soumya; Seo, Ji-Heui; Morova, Tunc; Hach, Faraz; Ding, Yi; Schwarz, Tommer; Huang, Chia-Chi Flora; Anderson, Jacob; Fay, Andre; Kalita, Cynthia; Groha, Stefan; Pomerantz, Mark; Wang, Victoria; Linder, Simon; Sweeney, Christopher; Zwart, Wilbert; Lack, Nathan A.; Pasaniuc, Bogdan; Takeda, David; Gusev, Alexander; Freedman, MatthewAbstractMethods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.