14666 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

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• Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy

  Esophageal adenocarcinomas (EACs) are associated with dismal prognosis. Deciphering the evolutionary histories of this disease may shed light on therapeutically tractable targets and reveal changing mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable EACs both before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of EACs with the presence of heterogeneous driver mutations, parallel evolution, early genome doubling events and an association between high intratumor heterogeneity and poor response to NAC. Multi-region sequencing demonstrated a significant reduction in T>G mutations within a CTT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of C>A mutations within a CpC context following NAC. EACs are characterized by the presence of amplifications containing targetable oncogenes present before and after chemotherapy that may provide a rationale for future therapeutic approaches.

  Study EGAS00001001254

• RNA_seq_of_Toxoplasma_gondii_response_in_human_macrophages

  Toxoplasmosis is a zoonotic disease caused by a ubiquitous protozoan parasite called Toxoplasma gondii, which caninfect all mammal and bird species throughout the world. seroprevalence varies widely between countries. Studieshave estimated that between 7-34% of people in the UK have been infected with T. gondii. The vast majority of thesepeople will not have noticed any symptoms, however about 10% of people develop a mild to moderate self limitingflu-like illness. Following the acute active stage of the infection the parasite persists in the body in the form of cysts,particularly in heart and skeletal muscle and nervous system tissues, for many years, and usually for life. Inimmunocompetent persons these cysts do not pose a health risk. We will use RNA-seq to quantify the transcriptionalresponse of macrophages to T gondii infection.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001708

• Novel mutational mechanisms and drivers in Pancreatic Neuroendocrine Tumours

  Pancreatic neuroendocrine tumours (PanNETs) are increasing in prevalence due to earlier detection, consequently creating challenges in clinical care, as current classification permits unsatisfactory therapeutic stratification. We performed whole genome sequencing of 102 primary PanNETs and defined the genomic events underlying their pathogenesis. We describe the mutational signatures they harbour, including a novel G:C>T:A Base-Excision-Repair-deficiency signature due to MUTYH inactivation. We uncover a larger than expected proportion of germline mutations in clinically sporadic PanNETs. These include previously unreported mutations in DNA repair genes MUTYH, CHEK2, BRCA2, and PALB2, which together with MEN1 and VHL occur in 16% of patients. Somatic mutations (point mutations and structural rearrangements) commonly occurred in genes involved in 4 main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including novel EWSR1 gene fusions) and telomere maintenance. Aberrations in these mechanisms are associated with subtypes of PanNET with potential clinical application for prognostic and therapeutic stratification.

  Study EGAS00001001732

• Complete Genomics paired end sequencing; Ovarian cancer

  We sequenced the genomes from a monozygotic twin discordant for schizophrenia and a tumor-normal pair of an ovarian cancer patient. Using whole-genome twin data to discriminate between correctly identified single nucleotide variants (SNVs) and errors a strategy for the accurate detection of SNVs was developed. By applying stringent sequencing quality measures, excluding error-prone regions and selecting SNVs identified by different mapping and variation calling algorithms, error rates were ~37-fold reduced. This enabled us to identify the first discordant SNVs in monozygotic twins using whole-genome sequencing. In addition, by showing that novel SNVs are highly enriched in errors, accurate estimates of the number of novel and rare SNVs occurring in unrelated Caucasian individuals were obtained. Finally, somatic mutations in coding and regulatory sequences were reliably identified in the highly rearranged ovarian tumor. Overall, our data demonstrate that strategies to reduce error rates in whole-genomes are required for disease gene discovery.

  Study EGAS00001000158

• Association of Age at Diagnosis and Genetic Mutations in Patients with Neuroblastoma

  Neuroblastoma is diagnosed over a wide age range from birth through young adulthood, and older age at diagnosis is associated with a decline in survivability. We performed whole genome sequencing of DNA from diagnostic tumors and their matched germlines from 40 patients with metastatic neuroblastoma obtained between 1987 and 2009. To identify genetic lesions that are associated with age at diagnosis in patients with metastatic neuroblastoma. Age groups at diagnosis included infants (0-18 months), children (18 months-12 years), and adolescents and young adults (>12 years). To confirm the findings from this discovery cohort, validation testing using tumors from an additional 64 patients obtained between 1985 and 2009 was also performed. Formalin-fixed paraffin-embedded tumor tissue was used for immunohistochemistry and fluorescent in situ hybridization. Telomere lengths were analyzed using the whole genome sequencing data, quantitative polymerase chain reaction and fluorescent in situ hybridization

  Study EGAS00001000213

• Genome Landscape of High-Grade Serous Ovarian Cancer

  Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

  Study EGAS00001000397

• High number of somatic mutations found in the healthy blood compartment of a 115-year-old woman reveals oligoclonal hematopoiesis

  The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole genome sequencing, we estimate that ~450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment of a 115-year old woman. The detected mutations appear to have been harmless passenger mutations: they were enriched in non-coding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes.The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

  Study EGAS00001000660

• Integrated genetic and epigenetic analysis defines novel molecular clusters in rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. To unravel the genetic/epigenetic basis of RMS, we studied 60 RMS cases using whole exome/transcriptome sequencing, copy number (CN) profiling, and DNA methylome analysis. Based on DNA methylation patterns, RMS was clustered into 4 distinct subtypes, which exhibited remarkable correlation with mutation/CN profiles, histological phenotypes, and clinical behaviors. A1 and A2 subtypes, especially A1, largely corresponded to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes were characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite generally poor prognosis in RMS, patients in E1 cluster exceptionally showed excellent prognosis. Our results highlight the close relationship between DNA methylation status and gene mutations and biological behavior in RMS.

  Study EGAS00001000884

• SeqControl: Process Control for DNA Sequencing

  As next-generation sequencing (NGS) continues to increase in speed and throughput, routine clinical and industrial application draws steadily closer. These “production” uses of NGS will require enhanced quality-monitoring and quality-control to optimize output and reduce costs. We therefore developed a framework called SeqControl for predicting sequencing quality and coverage using a set of 15 metrics describing overall coverage, coverage distribution, base-wise coverage and base-wise quality. Using whole-genome sequences of 27 prostate cancers and 26 normal references we derive multivariate models that predict sequencing quality and depth. SeqControl robustly predicts how much sequencing is required to reach a given coverage depth (AUC = 0.993), accurately classifies clinically relevant formalin-fixed paraffin-embedded samples and makes predictions from as little as 1/8 of a lane of sequencing data (AUC = 0.967). These techniques can be immediately incorporated into existing NGS pipelines to monitor data quality in real-time. SeqControl represents a first step towards statistical process-control for NGS.

  Study EGAS00001000899

• Genetic_profiling_of_mucosal_melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence ‘normal’ DNA from the same individual, where possible, to exclude germline variations.

  Study EGAS00001001115