Publications by authors named "Elias Rodriguez-Fos"

8 Publications

  • Page 1 of 1

Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma.

Nat Commun 2020 11 16;11(1):5823. Epub 2020 Nov 16.

Berlin Institute of Health, Anna-Louisa-Karsch-Str. 2, 10178, Berlin, Germany.

MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA (ecDNA). The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyze the MYCN amplicon structure using short-read and Nanopore sequencing and its chromatin landscape using ChIP-seq, ATAC-seq and Hi-C. This reveals two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplifies a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons is characterized by high structural complexity, lacks key local enhancers, and instead contains distal chromosomal fragments harboring CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.
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http://dx.doi.org/10.1038/s41467-020-19452-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669906PMC
November 2020

Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma.

Nat Genet 2020 01 16;52(1):29-34. Epub 2019 Dec 16.

Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.
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http://dx.doi.org/10.1038/s41588-019-0547-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008131PMC
January 2020

Publisher Correction: Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes.

Nat Commun 2018 05 30;9(1):2162. Epub 2018 May 30.

Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034, Barcelona, Spain.

In the originally published version of this Article, the affiliation details for Santi González, Jian'an Luan and Claudia Langenberg were inadvertently omitted. Santi González should have been affiliated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain', and Jian'an Luan and Claudia Langenberg should have been affiliated with 'MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK'. Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23, which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-04170-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976630PMC
May 2018

Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes.

Nat Commun 2018 01 22;9(1):321. Epub 2018 Jan 22.

Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034, Barcelona, Spain.

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.
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http://dx.doi.org/10.1038/s41467-017-02380-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778074PMC
January 2018

PGBD5 promotes site-specific oncogenic mutations in human tumors.

Nat Genet 2017 Jul 15;49(7):1005-1014. Epub 2017 May 15.

Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.
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http://dx.doi.org/10.1038/ng.3866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489359PMC
July 2017