11976 results for "cancer rna-seq"

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• MP2PRT: Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2", performs genomic characterization (WGS 30X, Total RNAseq, miRNAseq) on a discovery set of 70 trio cases (normal tissue, tumor tissue at time of diagnosis, tumor tissue at time of relapse) from patients who relapsed with Favorable Histology Wilms Tumor. Prioritized findings from the discovery set will be validated using Targeted Sequencing in an independent validation set of 47 relapse samples.

  Study phs001965

• The Ultrasound Study of Tamoxifen

  The Ultrasound Study of Tamoxifen is a 12-month longitudinal study to describe volumetric breast density change over time among women with and without tamoxifen exposure. Women were enrolled at the Karmanos Cancer Institute and Henry Ford Health Systems in Detroit, Michigan between 2011-2014. Enrollment included women prescribed tamoxifen for clinical indication (n=82) and a comparison group of women frequency matched on age, race, and menopausal status (n=165). Whole breast ultrasound tomography (UST) scans were used to measure volume averaged sound speed (m/s) as a surrogate of volumetric breast density. Ultrasound tomography (UST) scans were completed at baseline prior to tamoxifen initiation and were repeated at 1-3 months, 4-6 months, and 12 months after tamoxifen initiation. For the comparison group, UST scans were completed at baseline and 12 months. Questionnaires were completed at each scan.

  Study phs003183

• National Institutes of Health H3Africa African Collaborative Center for Microbiome and Genomics Research (ACCME)

  The African Collaborative Center for Microbiome and Genomics Research is a multi-institutional collaborative research project. The objectives of the project are to collaborate and implement high impact integrative epidemiology and genomics research into discovery of biomarkers associated with cervical carcinogenesis. Specifically ACCME links and leverages existing funded research and program activities at the collaborating institutions to study the interaction between vaginal microbiome, host genetic factors and molecular variants of Human Papilloma Virus (HPV) to determine correlates of viral persistence in the causal pathway of cervical cancer, a major cause of preventable mortality in Nigeria and other parts of sub-Saharan Africa. This research offers several opportunities to advance understanding of cervical carcinogenesis, viral oncogenesis, new biomarker discovery and risk stratification by genotype in a cohort of African women. Sponsorship: This project is sponsored by the National Institutes of Health (NIH)

  Study phs001945

• NHLBI TOPMed: Genetic Study of Atherosclerosis Risk (GeneSTAR)

  GeneSTAR began in 1982 as the Johns Hopkins Sibling and Family Heart Study, a prospective longitudinal family-based study conducted originally in healthy adult siblings of people with documented early onset coronary disease under 60 years of age. Commencing in 2003, the siblings, their offspring, and the coparent of the offspring participated in a 2 week trial of aspirin 81 mg/day with pre and post ex vivo platelet function assessed using multiple agonists in whole blood and platelet rich plasma. Extensive additional cardiovascular testing and risk assessment was done at baseline and serially. Follow-up was carried out to determine incident cardiovascular disease, stroke, peripheral arterial disease, diabetes, cancer, and related comorbidities, from 5 to 30 years after study entry. The goal of several additional phenotyping and interventional substudies has been to discover and amplify understanding of the mechanisms of atherogenic vascular diseases and attendant comorbidities.

  Study phs001218

• Functionally-defined Therapeutic Targets in Diffuse Intrinsic Pontine Glioma (DIPG)

  Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal childhood cancer. Here, we performed a chemical screen in patient-derived DIPG cell cultures along with RNAseq expression analysis and integrated computational modeling to identify potentially effective therapeutic strategies. Panobinostat, among the more promising agents identified, demonstrated efficacy in pontine orthotopic xenograft models of both H3K27M and histone WT DIPG. These data suggest the potential utility of specific drug combinations and provides evidence of in vivo treatment efficacy of the multi-histone deacetylase inhibitor panobinostat. We are depositing to dbGaP deep sequencing whole exome data for 22 patient tumor samples and 13 matched normals, along with RNAseq data for 12 patient tumor samples and 6 normal pediatric brain tissue samples. In addition, we are depositing 22 RNAseq samples from DIPG cell lines before and after panobinostat treatment.

  Study phs000900

• Xeroderma Pigmentosum, Complementation Group C, (XPC) and Non-XPC Cutaneous Squamous Cell Carcinoma (cSCC) Mutation Rate Study

  Base mutations occur at higher frequencies within heterochromatin and late-replicating DNA. In this study, we show that regional differences in mutation frequency are absent in portions of the genome that are not transcribed within cutaneous squamous cell carcinomas (cSCCs) with an XPC-\- genetic background. The XPC-\- genetic background predicates a loss of global genome nucleotide excision repair (GG-NER), thus our data shows that regional differences in mutation frequency are a result of differential access of DNA repair protein. Unexpectedly, we also note that greater transcription reduces mutations on both strands of genes in heterochromatin, and only to those levels observed in euchromatin, in a XPC-dependent fashion. Therefore, transcription likely reduces mutation prevalence by increasing access to DNA repair proteins. This tripartite relationship between DNA repair, transcription, and chromatin state shows a new cancer risk factor in human populations.

  Study phs000830

• NHLBI TOPMed - NHGRI CCDG: Malmo Preventive Project (MPP)

  The Malmö Preventive Project (MPP) was a community-based disease prevention program including 33,346 inhabitants from the city of Malmö in Southern Sweden. Complete birth cohorts between 1921-1949 were invited, and the participation rate was 71%. Participants underwent screening between 1974 to 1992 for cardiovascular risk factors, alcohol abuse, and breast cancer. Between 2002-2006, surviving participants were invited to a reexamination which included blood sampling from which DNA has been extracted. Subjects with prevalent or incident AF were identified from national registers as previously described, and cases with DNA were then matched in a 1:1 fashion to controls with DNA from the same cohort by sex, age (±1 year), and date of baseline exam (±1 year). Also, controls required a follow-up exceeding that of the corresponding AF case.

  Study phs001544

• Genetic Analysis of Skin Cells

  Cutaneous squamous cell carcinoma (cSCC) is a form of skin cancer originating from keratinocytes in the skin. They have high mutation burdens, primarily driven by UV-radiation-induced DNA damage. The order in which mutations undergo selection during the evolution of cSCC is not known. A subset of cSCCs grow out of benign neoplasms called actinic keratoses. To better understand the evolution of cSCC, we identified cases of cSCCs adjacent to actinic keratoses. From these cases, we separately microdissected the surrounding normal skin, the actinic keratosis, and the cSCC, and we performed targeted DNA-sequencing on the tissue from each area. We reconstructed tumor phylogenies and performed spatial transcriptomics on the 10X FFPE Visium platform on a subset of cases. Collectively, these studies revealed the mutational and gene expression changes that arise during the evolution of cSCC.

  Study phs003282

• Genomic Sequencing of Ewing Sarcoma

  Pediatric Ewing sarcoma is a pediatric cancer that primarily arises from the bone. It is characterized by chimeric fusions of the EWS gene and an ETS family transcription factor. In this study, we performed massively parallel sequencing of a larger collection of Ewing sarcoma tumors to define the genomic landscape of this disease. We found that these tumors are among of the most genetically normal cancers currently characterized. There was also a marked absence of recurrent mutations in immediately targetable signaling transduction pathway genes. In this study we answer outstanding questions about ETS transcription factor expression, effects of treatment on mutational burden in Ewing sarcoma tumors, and describe patterns of tumor evolution. We also found that loss-of-function mutations in STAG2 were present in approximately 15% of Ewing sarcoma tumors and loss of STAG2 expression was associated with disease metastasis in this patient cohort.

  Study phs000804

• The Formation and Propagation of Human Robertsonian Chromosomes

  Robertsonian chromosomes are a type of variant chromosome found commonly in nature. Present in one in 800 humans, these chromosomes can underlie infertility, trisomies, and increased cancer incidence. Recognized cytogenetically for more than a century, their origins have remained mysterious. Recent advances in genomics have allowed us to assemble three human Robertsonian chromosomes completely. We identify a common breakpoint and epigenetic changes in centromeres that provide insight into the formation and propagation of common Robertsonian translocations. Further investigation of the assembled genomes of chimpanzee and bonobo highlights the structural features of the human genome that uniquely enable the specific crossover event that creates these chromosomes. Resolving the structure and epigenetic features of human Robertsonian chromosomes at a molecular level will pave the way to understanding how chromosomal structural variation occurs more generally, and how chromosomes evolve.

  Study phs003920

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Study EGAS50000001328

• RNAseq_of_healthy_mesothelial_cells_and_primary_mesothelioma_cell_lines

  Mesothelioma is a rare and aggressive cancer associated with previous exposure to asbestos. Currently there are no effective treatments for mesothelioma and majority of patients will die within a year after diagnosis. Although a large number of preclinical and clinical trials assessed the efficacy of various therapuetic modes, including anti-angiogenic therapies, immunotherapy, antibody-drug conjugates and oncolytic viruses, none of the tested molecules entered the clinic. Thus, to better understand what drives mesothelioma carcinogenesis and to identify novel targets for therapy, in this project we aim at performing a comprehensive transcriptomic analysis of heathy mesothelial cells and a panel of mesothelioma cells lines. Primary mesothelial cell lines were established in prof. Marciniak lab from human pleural specimens, while primary mesothelioma cell lines were obtained from MesobanK. Both models constitute low passage cell lines and therefore should closely represent genetics of the original tissue.

  Study EGAS00001005728

• Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

  Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n¼54), genome/exome (n¼44) and transcriptome (n¼69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatinremodelling genes is sufficient to drive transformation in pulmonary carcinoids.

  Study EGAS00001000650

• Colorectal advanced adenomas NKI-AvL TGO COCOS series

  Colorectal cancer (CRC) develops from normal epithelium, through a benign precursor lesion called adenoma, by accumulation of genetic alterations affecting oncogenes and tumour suppressor genes. About 5% of colorectal adenomas are estimated to progress to CRC. However, it is important to identify which adenomas actually carry a high-risk of progression, because these serve as intermediate endpoints for e.g. screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high-risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression.For this tissue dataset, we applied low-pass whole genome sequencing to 96 advanced adenomas. Advanced adenomas were classified as lesions with low-risk or high-risk of progression, according to the presence of specific DNA copy number changes (Carvalho et al, CancerPrevRes, 2018).

  Study EGAS00001002952

• Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling

  Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts. Enhancer regions revealed novel oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, increased survival and slowed proliferation in mouse and neurosphere patient-derived models of ependymomas. This study represents one of the largest enhancer mapping study of any cancer type to date, and provides a framework for target and drug discovery for other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

  Study EGAS00001002696

• Genomic Heterogeneity and the Small Renal Mass

  Tumor heterogeneity is believed to represent a barrier to pre-operative genomic characterization in kidney cancer. Previous studies of heterogeneity in clear cell renal cell carcinoma (ccRCC) evaluated only large and metastatic tumors. In small renal tumors in which multiple biopsies are not feasible, the extent of heterogeneity remains unknown. In this study, we evaluated how the extent of genomic heterogeneity in small and large ccRCC. A total of 23 small (<4cm ) and 24 large (>7cm ) ccRCC had 3 regions sampled for evaluation of copy number, clear-cell A/clear-cell B (ccA/ccB) classification, and cell cycle progression (CCP) score. Small tumors have less genomic complexity and significantly fewer subclonal events. Pre-treatment genomic characterization based on a single biopsy in small ccRCC can provide insight into biologic potential to make clinical decisions.

  Study EGAS00001002919

• Whole exome sequencing reveals the mutational spectrum of testicular germ cell tumours

  Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole exome sequencing of 42 TGCTs to comprehensively study the mutational profile of TGCT. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per megabase [Mb]) as compared to the common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.

  Study EGAS00001001084

• multi-OMICs study of a pair of infant monozygotic twins with concordant B-cell ALL

  B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the genetic and the epigenetic landscape of this particular leukemia subtype, we performed whole genome DNA-, B-cell receptor (BCR)-, and DNA bisulfite-sequencing on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

  Study EGAS00001003651

• Transcriptional_Consequences_of_Copy_Number_Changes_MY_HDBR_200531

  Every normal human cell has two copies of each non-sex chromosome. The gain or loss of an extra copy underlies many health conditions, including developmental syndromes and cancer. Ultimately, it is the patterns of genes that are turned on and off that determines which proteins a cell produces and its biological function. Despite the importance of changes in chromosome number (known as aneuploidy or copy number changes), little is known about how these changes impact patterns of gene expression. This project will aim to fill this gap by creating an atlas of patterns of gene expression in cells from developmental tissues with aberrant numbers of chromosomes. These gene expression profiles will then be compared to the patterns of expression in the same cells with two copies of each chromosome, directly measuring the precise, cell specific, consequences of copy number change on gene expression.

  Study EGAS00001005100

• Accurate mapping of mitochondrial DNA deletions and duplications using deep sequencing

  Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology that can readily detect and discriminate between these two types of events is lacking. Here we present MitoSAlt, a computational method for accurate identification, quantification and visualization of mtDNA deletions and duplications from whole genome, whole exome or transcriptome sequencing data. MitoSAlt was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease further demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy. MitoSAlt paves the way for simple and reliable determination of mtDNA deletions and duplications across a wide range of relevant conditions and available sequencing datasets.  

  Study EGAS00001004380

• Whole exome sequencing data of germline and two independent primary leukemias of five patients

  The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this auto-regulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.

  Study EGAS00001001889

• Novel mutations in TOP2A in gliomas

  High grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. To better understand glioma pathobiology and find potential therapeutic susceptibilities, we designed a custom- panel 664 cancer- and epigenetics-related genes and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 glioma samples of different malignancy grades. Besides known alterations in TP53, IDH1, ATRX, EGFR genes, we found several novel variants that can be potential drivers in gliomas. In four patients from the Polish glioma cohort, we identified a novel recurrent mutation in the TOP2A gene coding for Topoisomerase 2A in glioblastomas (GBM, WHO grade IV gliomas). The mutation results in a substitution of glutamic acid (E) 948 to glutamine (Q) of TOP2 A and we predicted this E948Q substitution may affect DNA binding and a TOP2A enzymatic activity.

  Study EGAS00001004556

• Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions

  Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.

  Study EGAS00001006293

• single-stranded DNA study

  A ssDNA library protocol was applied to cfDNA from plasma samples obtained from different DNA extraction methods and revealed significant differences in DNA fragmentation patterns in comparison to dsDNA-based protocols. In particular, a specific combination of methods revealed a population of ultrashort fragments, organized at ~50 bp. We observed significant differences in the relative abundance of these ultrashort DNA fragments in plasma from healthy individuals and cancer patients. Through shallow whole genome sequencing (sWGS, <0.5-fold coverage) and the analysis of somatic copy number aberrations (SCNA), we determined the landscape of genetic alterations in this newly identified population of cfDNA fragments. In addition, we studied their potential link with regulatory regions by investigating the genome-wide coverage patterns at transcription start sites (TSS). Furthermore, we demonstrated that the ultrashort cfDNA fragments map to regions associated with secondary DNA structures, G-quadruplexes (G4s).

  Study EGAS00001005093

• How mitochondrial DNA research can benefit from data reuse through EGA?

  Mitochondria are the only cellular organelles harbouring their own DNA, which encodes for proteins essentials in its respiration process. Despite its discovery in 1960, Mitochondrial DNA is often overlooked compared to nuclear DNA. Indeed, not all sequencing technologies capture a good representation of mtDNA (mitochondrial DNA). Recently, Ed Reznik's team (The Ed Reznik Lab | Memorial Sloan Kettering Cancer Center) carried out a massive analysis and reanalysis of single cells WGS (whole genome sequencing) produced with an amplification-free protocol (Direct library prep, DLP). As they demonstrated in the paper Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes - PMC, DLP is more effective in catching mtDNA compared to classical single-cell sequencing. These data allowed the team to unravel mtDNA dynamics in tumoral and normal samples, highlighting how mtDNA and nuclear DNA are co-regulated and their ratio is critical for phenotype. Data reuse to achieve the greatest results For this project, Reznik's team re-used data from 3 studies stored at the European Genome-phenome Archive (EGAS00001006343, EGAS00001004448 and EGAS00001003190) that comprised a total of 602 datasets. All of them were initially produced by the teams of Sam Aparicio and Sohrab P. Shah at the Memorial Sloan Kettering Cancer Centre, where Ed Reznik is a promising group leader. This demonstrates, once again, that networking, collaboration and data sharing can achieve the greatest results when coupled with innovative and smart ideas. At the EGA we are proud to provide the scientific community with an infrastructure to enable all those very smart ideas out there to find the right data to be tested.

  Blog mitochondrial-dna-research