Publications (58) View all

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    Article: Punctuated evolution of prostate cancer genomes.
    Sylvan C Baca, Davide Prandi, Michael S Lawrence, Juan Miguel Mosquera, Alessandro Romanel, Yotam Drier, Kyung Park, Naoki Kitabayashi, Theresa Y Macdonald, Mahmoud Ghandi, [......], Michael F Berger, Stacey B Gabriel, Todd R Golub, Matthew Meyerson, Eric S Lander, Olivier Elemento, Gad Getz, Francesca Demichelis, Mark A Rubin, Levi A Garraway
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    ABSTRACT: The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy," frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.
    Cell 04/2013; 153(3):666-77. · 32.40 Impact Factor
  • Article: Epigenomic alterations in localized and advanced prostate cancer.
    Pei-Chun Lin, Eugenia G Giannopoulou, Kyung Park, Juan Miguel Mosquera, Andrea Sboner, Ashutosh K Tewari, Levi A Garraway, Himisha Beltran, Mark A Rubin, Olivier Elemento
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    ABSTRACT: Although prostate cancer (PCa) is the second leading cause of cancer death among men worldwide, not all men diagnosed with PCa will die from the disease. A critical challenge, therefore, is to distinguish indolent PCa from more advanced forms to guide appropriate treatment decisions. We used Enhanced Reduced Representation Bisulfite Sequencing, a genome-wide high-coverage single-base resolution DNA methylation method to profile seven localized PCa samples, seven matched benign prostate tissues, and six aggressive castration-resistant prostate cancer (CRPC) samples. We integrated these data with RNA-seq and whole-genome DNA-seq data to comprehensively characterize the PCa methylome, detect changes associated with disease progression, and identify novel candidate prognostic biomarkers. Our analyses revealed the correlation of cytosine guanine dinucleotide island (CGI)-specific hypermethylation with disease severity and association of certain breakpoints (deletion, tandem duplications, and interchromosomal translocations) with DNA methylation. Furthermore, integrative analysis of methylation and single-nucleotide polymorphisms (SNPs) uncovered widespread allele-specific methylation (ASM) for the first time in PCa. We found that most DNA methylation changes occurred in the context of ASM, suggesting that variations in tumor epigenetic landscape of individuals are partly mediated by genetic differences, which may affect PCa disease progression. We further selected a panel of 13 CGIs demonstrating increased DNA methylation with disease progression and validated this panel in an independent cohort of 20 benign prostate tissues, 16 PCa, and 8 aggressive CRPCs. These results warrant clinical evaluation in larger cohorts to help distinguish indolent PCa from advanced disease.
    Neoplasia (New York, N.Y.) 04/2013; 15(4):373-83. · 5.48 Impact Factor
  • Article: Identifying an ERG-positive Subclass with Clinical Progression Using Expression Profiling.
    Andrea Sboner, Mark A Rubin
    European urology 03/2013; · 7.67 Impact Factor
  • Article: Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma.
    Juan Miguel Mosquera, Andrea Sboner, Lei Zhang, Naoki Kitabayashi, Chun-Liang Chen, Yun Shao Sung, Leonard H Wexler, Michael P Laquaglia, Morris Edelman, Chandrika Sreekantaiah, Mark A Rubin, Cristina R Antonescu
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    ABSTRACT: Spindle cell rhabdomyosarcoma (RMS) is a rare form of RMS with different clinical characteristics between children and adult patients. Its genetic hallmark remains unknown and it remains debatable if there is pathogenetic relationship between the spindle cell and the so-called sclerosing RMS. We studied two pediatric and one adult spindle cell RMS by next generation RNA sequencing and FusionSeq data analysis to detect novel fusions. An SRF-NCOA2 fusion was detected in a spindle cell RMS from the posterior neck in a 7-month-old child. The fusion matched the tumor karyotype and was confirmed by FISH and RT-PCR, which showed fusion of SRF exon 6 to NCOA2 exon 12. Additional 14 spindle cell (from 8 children and 6 adults) and 4 sclerosing (from 2 children and 2 adults) RMS were tested by FISH for the presence of abnormalities in NCOA2, SRF, as well as for PAX3 and NCOA1. NCOA2 rearrangements were found in two additional spindle cell RMS from a 3-month-old and a 4-week-old child. In the latter tumor, TEAD1 was identified by rapid amplification of cDNA ends (RACE) to be the NCOA2 gene fusion partner. None of the adult tumors were positive for NCOA2 rearrangement. Despite similar histomorphology in adults and young children, these results suggest that spindle cell RMS is a heterogeneous disease genetically as well as clinically. Our findings also support a relationship between NCOA2-rearranged spindle cell RMS occurring in young childhood and the so-called congenital RMS, which often displays rearrangements at 8q13 locus (NCOA2). © 2013 Wiley-Liss,Inc.
    Genes Chromosomes and Cancer 03/2013; · 3.31 Impact Factor
  • Article: VAT: a computational framework to functionally annotate variants in personal genomes within a cloud-computing environment.
    Lukas Habegger, Suganthi Balasubramanian, David Z Chen, Ekta Khurana, Andrea Sboner, Arif Harmanci, Joel Rozowsky, Declan Clarke, Michael Snyder, Mark Gerstein
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    ABSTRACT: The functional annotation of variants obtained through sequencing projects is generally assumed to be a simple intersection of genomic coordinates with genomic features. However, complexities arise for several reasons, including the differential effects of a variant on alternatively spliced transcripts, as well as the difficulty in assessing the impact of small insertions/deletions and large structural variants. Taking these factors into consideration, we developed the Variant Annotation Tool (VAT) to functionally annotate variants from multiple personal genomes at the transcript level as well as obtain summary statistics across genes and individuals. VAT also allows visualization of the effects of different variants, integrates allele frequencies and genotype data from the underlying individuals and facilitates comparative analysis between different groups of individuals. VAT can either be run through a command-line interface or as a web application. Finally, in order to enable on-demand access and to minimize unnecessary transfers of large data files, VAT can be run as a virtual machine in a cloud-computing environment. AVAILABILITY AND IMPLEMENTATION: VAT is implemented in C and PHP. The VAT web service, Amazon Machine Image, source code and detailed documentation are available at vat.gersteinlab.org.
    Bioinformatics 06/2012; 28(17):2267-9. · 5.47 Impact Factor

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