14662 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

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• Patient-derived pediatric brain tumor organoids faithfully recapitulate primary tumors

  Extensive molecular analysis by many groups has revealed a heterogeneous landscape of embryonal brain tumors, including medulloblastoma (MB) and atypical teratoid/rhabdoid tumor (ATRT). MB, the most common malignant pediatric brain tumor, is comprised of four molecularly distinct subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3), and Group 4 (G4). Among these, MB-SHH harboring MYCN amplification and TP53 mutation and MB-G3 with MYC overexpression or amplification constitute the most aggressive tumors, have the poorest clinical outcomes, and lack effective therapeutic options for recurrent disease. Here we describe the establishment of tumor organoid (TO) models from patient-derived orthotopic xenografts (PDOX) of MYCN-amplified and TP53-mutant MB-SHH, MYC-amplified MB-G3 and two ATRT which all grew in mice when reimplanted into the cortices of naïve recipient animals (TOX). Methylation, bulk and single-cell RNA sequencing, and whole genome sequencing demonstrated that TOs and TOXs faithfully recapitulated the molecular landscape and heterogeneity of PDOXs and primary patient tumors compared to established cell lines. The development of TOs will facilitate in vitro high-throughput drug or CRISPR screens without the need for use tumor-bearing mice. This will also accelerate the identification and validation of new vulnerabilities and in vivo preclinical testing toward clinical trials.

  Study EGAS00001008305

• Botswana 15 autosomal unlinked microsatellites

  Population structure was investigated in 990 Botswana individuals according to ethno-linguistics, Bantu and Khoisan, and geography (the nine administrative districts) using the AmpFLSTR Identifiler autosomal microsatellite markers. Genetic diversity and forensic parameters were calculated for the overall population, and according to ethno-linguistics and geography. The overall combined power of exclusion (CPE) was 0.9999965412 and the combined match probability 6,28 x 10-19. CPE was highest for the Khoisan Tuu ethnolinguistic group and the Northeast District at 0.9999582029 and 0.9999922652 respectively. CMP ranged from 6.28 x 10-19 (Khoisan Tuu) to 1,02 x 10-18 (Northwest district). Using pairwise genetic distances (FST), analysis of molecular variance (AMOVA), factorial correspondence analysis (FCA), and the unsupervised Bayesian clustering method found in STRUCTURE and landscape genetics software TESS, ethno-linguistics were found to have a greater influence on population structure than geography. FCA showed clustering between Bantu and Khoisan, and within the Bantu. This Bantu sub-structuring was not seen with STRUCTURE and TESS, which detected clustering only between Bantu and Khoisan. The patterns of population structure revealed highlight the need for regional reference databases that include ethno-linguistic and geographic location information. These markers have important potential for bio-anthropological studies as well as for forensic applications.

  Study EGAS00001002380

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC -- CA209-009

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Study EGAS00001004290

• Allele Balance Bias Identifies Systematic Genotyping Errors and False Disease Associations

  In recent years, Next Generation Sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many clinical applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing rare diseases need to be identified. Although random sequencing errors can be modeled statistically and deep sequencing minimizes their impact, systematic errors remain a problem even at high depth of coverage. Understanding their source is crucial to increase precision of clinical NGS applications. In this work, we studied the relation between recurrent biases in allele balance (AB), systematic errors and false positive variant calls across a large cohort of human samples analyzed by whole exome sequencing (WES). We have modeled the allele balance distribution for biallelic genotypes in 987 WES samples in order to identify positions recurrently deviating significantly from the expectation, a phenomenon we termed allele balance bias (ABB). Furthermore, we have developed a genotype callability score based on ABB for all positions of the human exome, which detects false positive variant calls that passed state-of-the-art filters. Finally, we demonstrate the use of ABB for detection of false associations proposed by rare variant association studies (RVAS).

  Study EGAS00001003027

• Intratumoural Heterogeneity Underlies Distinct Therapy Responses and Treatment Resistance in Glioblastoma

  Glioblastomas are the most common and lethal neoplasms of the central nervous system. Neighbouring glioma cells maintain extreme degrees of genetic and phenotypic variation that forms intratumoural heterogeneity. This genetic diversity allows the most adaptive tumour clones to show treatment resistance and conserve the tumour bulk. We aimed to model this phenomenon and test the effectiveness of several targeted therapeutic interventions to overcome therapy resistance. Heterogenic tumour masses were first deconstructed into single tumour cells, which were expanded independently as single-cell clones. SNP arrays, whole-genome and RNA sequencing, and CpG methylation analysis validated the unique molecular profile of each tumour clone, which displayed distinct pathologic features, including cell morphology, growth rate, and resistance to temozolomide and ionizing radiation. We also identified variable sensitivities to AURK, CDK, and EGFR inhibitors, consistent with the heterogenic molecular alterations that each clone harboured. These targeted therapies effectively eliminated the temozolomide- and/or irradiation-resistant clones and also parental polyclonal cells. Our findings indicate that polyclonal tumours create a dynamic environment that consists of diverse tumour elements and treatment responses. Designing targeted therapies based on a range of molecular profiles can be a more effective strategy to eradicate treatment resistance, recurrence, and metastasis.

  Study EGAS00001003438

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal_LCM

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003455

• The evolutionary trajectory of a highly recurrent paediatric high grade neuroepithelial tumour with MN1:BEND2 fusion

  Astroblastomas are rare brain tumours which predominate in children and young adults, and have a controversial claim as a distinct entity, with no established WHO grade. Reports suggest a better outcome than high grade gliomas, though they frequently recur. Recently, they have been described to overlap with a newly-discovered group of tumours described as ’high grade neuroepithelial tumour with MN1 alteration’ (CNS HGNET-MN1), defined by global methylation patterns and strongly associated with gene fusions targeting MN1. We have studied a unique case of astroblastoma arising in a 6 year old girl, with multiple recurrences over a period of 10 years, with the pathognomonic MN1:BEND2 fusion. Exome sequencing allowed for a phylogenetic reconstruction of tumour evolution, which when integrated with clinical, pathological and radiological data provide for a thorough understanding of disease progression, with initial treatment driving tumour dissemination along four distinct trajectories. Infiltration of distant sites was associated with a later genome doubling, whilst there was evidence of convergent evolution of different lesions acquiring distinct alterations targeting NF-κB. These data represent an usual opportunity to understand the evolutionary history of a highly recurrent childhood brain tumour, and provide novel therapeutic targets for astroblastoma / CNS HGNET-MN1.

  Study EGAS00001002432

• Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

  Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression. Systematic annotation of genome wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing and allele specific expression are each important determinants of the DCM phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. (*) numbers in parentheses represent samples that the publication is based on.

  Study EGAS00001002454

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal

  he Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003774

• Characterizing microbiome-directed fibre snacks in gnotobiotic mice and humans

  Knowledge of the interrelationships between what we eat and the configurations of our gut microbial communities is providing important insights into how food components that are not directly metabolized by human enzymes are linked to our physiology and health status. Changing food preferences brought about by Westernization that have deleterious health effects1,2, plus rapid population expansion, ongoing challenges to sustainable agriculture, and other forces contributing to increased food insecurity, are catalyzing efforts to identify more nutritious and affordable foods3. The gut microbial community is complex, dynamic, and exhibits considerable intra- and interpersonal variation in its composition and functions. The massive number of potential interactions between its components makes it challenging to define the mechanisms by which food ingredients affect community properties. There is also a paucity of information about the ‘bioactive’ ingredients of foods that influence the fitness and expressed functions of community members. Here, plant fibres, from different sustainable sources and targeting distinct features of obese human gut microbiomes in gnotobiotic mice, were formulated into snack prototypes and used to supplement controlled diets consumed by overweight and obese adults; the results revealed fibre-specific changes in their microbiomes that were linked to changes in their plasma proteomes indicative of altered physiologic state.

  Study EGAS00001005268