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Transposon insertion profiling by sequencing (TIPseq) for mapping LINE-1 insertions in the human genome

Steranka, Jared P; Tang, Zuojian; Grivainis, Mark; Huang, Cheng Ran Lisa; Payer, Lindsay M; Rego, Fernanda O R; Miller, Thiago Luiz Araujo; Galante, Pedro A F; Ramaswami, Sitharam; Heguy, Adriana; Fenyö, David; Boeke, Jef D; Burns, Kathleen H
Background/UNASSIGNED:Transposable elements make up a significant portion of the human genome. Accurately locating these mobile DNAs is vital to understand their role as a source of structural variation and somatic mutation. To this end, laboratories have developed strategies to selectively amplify or otherwise enrich transposable element insertion sites in genomic DNA. Results/UNASSIGNED:Here we describe a technique, Transposon Insertion Profiling by sequencing (TIPseq), to map Long INterspersed Element 1 (LINE-1, L1) retrotransposon insertions in the human genome. This method uses vectorette PCR to amplify species-specific L1 (L1PA1) insertion sites followed by paired-end Illumina sequencing. In addition to providing a step-by-step molecular biology protocol, we offer users a guide to our pipeline for data analysis, TIPseqHunter. Our recent studies in pancreatic and ovarian cancer demonstrate the ability of TIPseq to identify invariant (fixed), polymorphic (inherited variants), as well as somatically-acquired L1 insertions that distinguish cancer genomes from a patient's constitutional make-up. Conclusions/UNASSIGNED:TIPseq provides an approach for amplifying evolutionarily young, active transposable element insertion sites from genomic DNA. Our rationale and variations on this protocol may be useful to those mapping L1 and other mobile elements in complex genomes.
PMCID:6407172
PMID: 30899333
ISSN: 1759-8753
CID: 3734532

Multifocal Breast Cancer: A Clonality Study Using Whole Exome Sequencing [Meeting Abstract]

Schwartz, Christopher; Dolgalev, Igor; Heguy, Adriana; Snuderl, Matija; Jour, George; Darvishian, Farbod
ISI:000478915500253
ISSN: 0893-3952
CID: 4048052

Multifocal Breast Cancer: A Clonality Study Using Whole Exome Sequencing [Meeting Abstract]

Schwartz, Christopher; Dolgalev, Igor; Heguy, Adriana; Snuderl, Matija; Jour, George; Darvishian, Farbod
ISI:000478081100253
ISSN: 0023-6837
CID: 4048322

Correction: The fecal, oral, and skin microbiota of children with Chagas disease treated with benznidazole

Robello, Carlos; Maldonado, Doris Patricia; Hevia, Anna; Hoashi, Marina; Frattaroli, Paola; Montacutti, Valentina; Heguy, Adriana; Dolgalev, Igor; Mojica, Maricruz; Iraola, Gregorio; Dominguez-Bello, Maria G
[This corrects the article DOI: 10.1371/journal.pone.0212593.].
PMID: 30947318
ISSN: 1932-6203
CID: 4095132

Radiotherapy induces responses of lung cancer to CTLA-4 blockade

Formenti, Silvia C; Rudqvist, Nils-Petter; Golden, Encouse; Cooper, Benjamin; Wennerberg, Erik; Lhuillier, Claire; Vanpouille-Box, Claire; Friedman, Kent; Ferrari de Andrade, Lucas; Wucherpfennig, Kai W; Heguy, Adriana; Imai, Naoko; Gnjatic, Sacha; Emerson, Ryan O; Zhou, Xi Kathy; Zhang, Tuo; Chachoua, Abraham; Demaria, Sandra
Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1-3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor4-6. The latter is essential for achieving abscopal responses in murine cancers6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.
PMID: 30397353
ISSN: 1546-170x
CID: 3455792

Airway Microbiota Is Associated with Up-Regulation of the PI3K Pathway in Lung Cancer

Tsay, Jun-Chieh J; Wu, Benjamin G; Badri, Michelle H; Clemente, Jose C; Shen, Nan; Meyn, Peter; Li, Yonghua; Yie, Ting-An; Lhakhang, Tenzin; Olsen, Evan; Murthy, Vivek; Michaud, Gaetane; Sulaiman, Imran; Tsirigos, Aristotelis; Heguy, Adriana; Pass, Harvey; Weiden, Michael D; Rom, William N; Sterman, Daniel H; Bonneau, Richard; Blaser, Martin J; Segal, Leopoldo N
BACKGROUND:In lung cancer, upregulation of the PI3K pathway is an early event that contributes to cell proliferation, survival, and tissue invasion. Upregulation of this pathway was recently described as associated with enrichment of the lower airways with bacteria identified as oral commensals. We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways. METHODS:Airway brushes were collected prospectively from subjects with lung nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung cancer diagnoses and 36 subjects with non-cancer diagnosis. Additionally, samples from 10 healthy control subjects were included. 16S rRNA gene amplicon sequencing and paired transcriptome sequencing (RNAseq) were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed. RESULTS:The composition of the lower airway transcriptome in the cancer patients was significantly different from the controls, which included upregulation of ERK and PI3K signaling pathways. The lower airways of lung cancer patients were enriched for oral taxa (Streptococcus and Veillonella), which was associated with upregulation of the ERK and PI3K signaling pathways. In vitro exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus led to upregulation of these same signaling pathways. CONCLUSIONS:The data presented here shows that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.
PMID: 29864375
ISSN: 1535-4970
CID: 3144342

Identification of a whole blood signature for venous thromboembolism [Meeting Abstract]

Hogan, M; Zhou, H; Lhakhang, T; Barrett, T J; O'Reilly, D; Smilowitz, N; Heguy, A; Maldonado, T; Tsirigos, A; Berger, J
Venous thromboembolism (VTE), comprised of deep vein thrombosis and pulmonary embolism, is a common health problem both in the United States and worldwide, with significant associated morbidity and mortality. Despite multiple known genetic and situational risk factors, an estimated 30% of all events remain classified as idiopathic, demonstrating a significant knowledge gap in the pathophysiology VTE. While platelets are well established as an essential contributor to thrombus formation and there has been recent interest in the role of neutrophil extracellular traps, specific cell types and pathways involved in the pathogenesis of VTE remain uncertain. In this study, our primary aims were to define a unique transcriptional signature for VTE and to identify the types of cells and specific pathways involved in development of VTE. Whole blood was collected in PAX gene tubes and RNA sequencing for coding mRNA was performed in an unbiased manner in 201 patients with prevalent VTE as well as 43 healthy controls. We used a bioinformatics approach to develop a unique signature for VTE by identifying differentially expressed genes, developing cell-type modules, and ascertaining pathways driving differentially expressed transcripts. We performed additional analyses on subgroups of patients with idiopathic VTE, patients with incident VTE, and VTE patients matched to healthy controls by age and sex. We went on to use machine learning methods to learn models that best differentiate VTE patients from healthy controls and validated it on a left out test set within our VTE population. Genes specific to neutrophils, erythrocytes, and platelets, in that order, were most significantly upregulated in patients with VTE compared to healthy controls. Genes related to T-cells were downregulated. Pathway analysis revealed upregulated neutrophil activation and degranulation, erythrocyte differentiation and homeostasis, and platelet degranulation. A gene signature of 217 transcripts was outstanding at differentiating patients with VTE versus healthy controls (AUC 0.94). Following adjustment for age, sex, and race/ethnicity our genetic signature remained significantly robust at differentiating patients with VTE versus controls (AUC 0.83). Our expression signature remained stable across patients with idiopathic VTE (AUC 0.93), and in patients who went on to develop future VTE events (AUC 0.95). In summary, we have demonstrated a whole blood transcriptional signature for prevalent and incident VTE. Genes related to neutrophils, erythrocytes, and platelets are upregulated in patients with VTE and genes related to T-cells were downregulated. These findings suggest an active role of cell types once thought to be passively entrapped within thrombus and provide new areas of study to establish the pathophysiology of VTE
EMBASE:626460770
ISSN: 0006-4971
CID: 3703362

Human blastocysts of normal and abnormal karyotypes display distinct transcriptome profiles

Licciardi, Frederick; Lhakhang, Tenzin; Kramer, Yael G; Zhang, Yutong; Heguy, Adriana; Tsirigos, Aristotelis
Unveiling the transcriptome of human blastocysts can provide a wealth of important information regarding early embryonic ontology. Comparing the mRNA production of embryos with normal and abnormal karyotypes allows for a deeper understanding of the protein pathways leading to viability and aberrant fetal development. In addition, identifying transcripts specific for normal or abnormal chromosome copy number could aid in the search for secreted substances that could be used to non-invasively identify embryos best suited for IVF embryo transfer. Using RNA-seq, we characterized the transcriptome of 71 normally developing human blastocysts that were karyotypically normal vs. trisomic or monosomic. Every monosomy and trisomy of the autosomal and sex chromosomes were evaluated, mostly in duplicate. We first mapped the transcriptome of three normal embryos and found that a common core of more than 3,000 genes is expressed in all embryos. These genes represent pathways related to actively dividing cells, such as ribosome biogenesis and function, spliceosome, oxidative phosphorylation, cell cycle and metabolic pathways. We then compared transcriptome profiles of aneuploid embryos to those of normal embryos. We observed that non-viable embryos had a large number of dysregulated genes, some showing a hundred-fold difference in expression. On the contrary, sex chromosome abnormalities, XO and XXX displayed transcriptomes more closely mimicking those embryos with 23 normal chromosome pairs. Intriguingly, we identified a set of commonly deregulated genes in the majority of both trisomies and monosomies. This is the first paper demonstrating a comprehensive transcriptome delineation of karyotypic abnormalities found in the human pre-implantation embryo. We believe that this information will contribute to the development of new pre-implantation genetic screening methods as well as a better understanding of the underlying developmental abnormalities of abnormal embryos, fetuses and children.
PMID: 30297919
ISSN: 2045-2322
CID: 3334642

MOSAIC BLASTOCYSTS DIAGNOSED WITH NEXT GENERATION SEQUENCING (NGS) HAVE UNIQUE TRANSCRIPTOMIC PROFILES DIFFERENT FROM THOSE OF EUPLOID OR ANEUPLOID EMBRYOS. [Meeting Abstract]

Maxwell, S. M.; Lhakhang, T.; Kramer, Y. G.; Zhang, Y.; Heguy, A.; Tsirigos, A.; Grifo, J. A.; Licciardi, F.
ISI:000448713600189
ISSN: 0015-0282
CID: 3493792

Genome-wide mutational signature of glycidamide observed in human cancers using pcawg data [Meeting Abstract]

Zhivagui, M; Ng, A W T; Ardin, M; Churchwell, M I; Pandey, M; Renard, C; Villar, S; Cahais, V; Robitaille, A; Bouaoun, L; Heguy, A; Guyton, K; Stampfer, M R; McKay, J; Hollstein, M; Olivier, M; Rozen, S G; Beland, F A; Korenjak, M; Zavadil, J
Purpose: Acrylamide, a probable human carcinogen (Group 2A), is ubiquitously present in the human environment. The compound is found in heated starchy foods, coffee, as well as cigarette smoke. Humans are also exposed to acrylamide occupationally. The carcinogenicity of acrylamide has been attributed to the effects of glycidamide, its reactive and mutagenic epoxide metabolite shown to be an inducer of rodent tumors at various anatomical sites. Covalent adducts with haemoglobin were reported in humans exposed to acrylamide, and DNA adducts in experimental systems. Methods: In order to characterize the pre-mutagenic DNA lesions and global mutation spectra induced by acrylamide and glycidamide, we combined DNA-adduct and wholeexome sequencing analyses in an established exposureclonal immortalization system based on mouse embryonic fibroblasts. Results: Sequencing and computational analysis of cell clones immortalized after exposure revealed a unique mutational signature of glycidamide, characterized by predominant T:A>A:T transversions, T:A>C:G transitions and C:G>A:T transversions in specific trinucleotide contexts, and with significant transcription strand bias. Computational interrogation of the human pan-cancer genome sequencing data (PCAWG data set) using experimentally derived glycidamide signature revealed the presence of the glycidamide signature in lung adenocarcinomas, lung squamous cell carcinomas and liver cancer, manifesting as a sub-component of the COSMIC tobacco smoking-related signature 4, as well as possibly associated with dietary intake of acrylamide. Conclusions: Our study demonstrates how the controlled experimental characterization of specific genetic damage associated with glycidamide exposure facilitates identifying corresponding patterns in cancer genome data, thereby underscoring how mutational signature laboratory experimentation contributes to the elucidation of cancer causation
EMBASE:623841676
ISSN: 1098-2280
CID: 3302392