4076 results for "*geneti*"

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• 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

• HCA_Thymus_Disease

  Single cell RNA sequencing on thymic cells from children with syndromic diseases such as Trisomy 21 and inflammatory/autoimmune diseases such as myasthenia gravis. Our group has previously performed atlasing of the healthy human thymus using single cell transcriptomics and obtained an unprecedented understanding of human thymus throughout development. In this study, we intend to survey diseased human thymus and compare this to healthy to obtain a better understanding of thymic dysfunction in human diseases. The diseases we will survey include congenital conditions such as Down's syndrome, CHARGE syndrome, DiGeorge syndrome as well as acquired diseases such as myasthenia gravis and thymic hyperplasia. We intend to perform genetic and genomic study on the samples, including expression analysis. This will not only help us to understand the cells and molecular pathways affected in dysfunctional thymus; but may also lead to generalisable understandings in human genetic diseases and inflammatory/autoimmune diseases. 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 EGAS00001004310

• Comprehensive pharmacogenomic characterization of gastric cancer

  Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

  Study EGAS00001004106

• Persistent STAG2 mutation in recurrent pediatric glioblastoma

  Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious STAG2 mutation, whose deficiency in pre-clinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an EGFR mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently STAG2 mutated clone, with rare mutations in PTPN11 and BRAF, the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying STAG2 deficiency. As such, this case represents a novel report following the clinical and genetic progression of a STAG2 mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although STAG2 deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing pre-clinical data supporting a role for STAG2 mutations in tumor formation and resistance to standard therapies.

  Study EGAS00001004340

• Human genomic and phenotypic synthetic data for the study of rare diseases

  The purpose of this dataset is to facilitate development of technical implementations for rare disease data integration, analysis, discovery, and federated access. This synthetic dataset includes clinical and genomic data from 6 rare disease cases. It consists of 18 whole genomes (6 index cases with their parents) which have genetic background based on public human data sequenced in the context of the Illumina Platinum initiative (Eberle, MA et al. (2017)) and made available by the HapMap project (https://www.genome.gov/10001688/international-hapmap-project). In each of the cases, real causative variants correlating with the phenotypic data provided were spiked-in. The cases included in this synthetic dataset correspond to the following type of disorders: CASE 1- Congenital myasthenic syndrome (Autosomal Dominant -de novo variant) CASE 2- Macular dystrophy (Autosomal Dominant) CASE 3- Muscular dystrophy (Autosomal Recessive-compound heterozygous variants) CASE 4- Mitochondrial disorder (Autosomal Recessive-consanguineous case - homozygous variant) CASE 5- Breast cancer (Autosomal Dominant) CASE 6- Similar as case 1 for patient matchmaking tests: Congenital myasthenic syndrome (Autosomal Dominant-de novo variant) For each case you will be able to download the following data: clinical information (phenopackets per individual and pedigree per family), raw genomic data (FASTQ and BAMs) and processed genomic data (vcfs). When using the data, the following should be acknowledged: the RD-Connect GPAP (https://platform.rd-connect.eu/), EC H2020 project EJP-RD (grant # 825575), EC H2020 project B1MG (grant # 951724) and Generalitat de Catalunya VEIS project (grant # 001-P-001647).

  Study EGAS00001005702

• Targets of MEK inhibition in DIPG

  The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib in samples which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted an observed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.

  Study EGAS00001004495

• Whole-genome sequencing of rare disease patients in a national healthcare system

  Most patients with rare diseases do not receive a molecular diagnosis and the aetiologicalvariants and mediating genes for more than half such disorders remain to be discovered. Weimplemented whole-genome sequencing (WGS) in a national healthcare system to streamlinediagnosis and to discover unknown aetiological variants, in the coding and non-coding regionsof the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelianassociations between genes and rare diseases, of which 11 have been discovered since 2015and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rarealleles can explain the presence of some individuals in the tails of a quantitative red blood cell(RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through thedisruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates asynergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

  Study EGAS00001004364

• DERMATLAS__Porocarcinoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005721

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126

• Test Study for EGA using data from 1000 Genomes Project - Phase 3

  The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies...

  Study EGAS00001005042