250 results for "study_type:"exome sequencing" AND repository:ega"

in 31.87 milliseconds.

• Multi-region sequencing of PDAC patients

  Study EGAS00001007379

• Expanding CIRdb, a comprehensive catalog of whole-exome sequencing data of Canary Islanders

  This study aimed to comprehensively characterize the full spectrum of small genetic variation among 920 unrelated donors from this population based on whole-exome sequencing data to further develop CIRdb as the Canary Islanders-specific reference catalog of genetic variation.

  Study EGAS50000001726

• Targeting vulnerabilities in IDH mutant tumours: The model matters WES study

  Introduction: Synthetic lethal interactions with IDH1 and IDH2 (IDH) mutations were identified in non-endogenous IDH mutant (IDHmut) AML and glioma models, but are absent in endogenous IDHmut chondrosarcoma cell lines. The translation into successful clinical applications has remained challenging, implying artificially created models do not fully recapitulate endogenous IDHmut tumour biology. The aim of this study was to elucidate if the model system is indeed an important factor to consider when studying therapeutic vulnerabilities in IDHmut tumours. Methods: Vector-based and CRISPR-Cas9 approaches were used to introduce or revert the IDH1 mutation in chondrosarcoma cell lines. These isogenic cell line pairs were used to examine the presence of known therapeutic vulnerabilities and their underlying biological mechanisms. Results: Vector-based IDHmut chondrosarcoma models showed the previously reported synthetic lethal interactions, but these treatment sensitivities were absent in the CRISPR-edited models. Interestingly, not all vector-based IDHmut cell lines displayed the same therapeutic vulnerabilities. Differences in treatment response were associated with multiple factors, including IDHmut protein expression and D-2-HG levels, in line with the fact that therapeutic vulnerabilities could be induced in the CRISPR-edited models by enhancing D-2-HG levels. Conclusion: Our findings demonstrate that synthetic lethal interactions observed in vector-based models are often a consequence of IDHmut protein overexpression and supra-physiological D-2-HG levels. These results highlight that relying on artificially created IDHmut models may lead to the identification of therapeutic vulnerabilities that are not present in IDHmut tumours, potentially explaining the poor translation of preclinical findings to clinical trials.

  Study EGAS50000001870

• Pancreatic Cancer Sequencing Initiative

  Pancreatic Cancer Sequencing Initiative for the International Cancer Genome Consortium at the Ontario Institute for Cancer Research.

  Study EGAS00001000343

• Whole-exome Sequencing Combined with Functional Genomics Reveals Novel Candidate Driver Cancer Genes in Endometrial Cancer

  Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we developed an integrated systems biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1 and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the “sensor” cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.

  Study EGAS00001000318

• Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma

  Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations inTP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

  Study EGAS00001000579

• UK10K_RARE_HYPERCHOL

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.Familial Hypercholesterolemia is a condition where the affected person has a consistently high level of LDL which can lead to early clogging of the coronary arteries. All patients selected for this study will have been found not to carry the common APOB and PCSK9 mutations, and to have no detectable LDLR mutations by testing for 18 common mutations. For further information with regard to this cohort please contact Steve Humphries(steve.humphries@ucl.ac.uk).

  Study EGAS00001000129

• Ashkenazi Jewish Leukoencephalopathy

  Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities in the central nervous system (CNS). Patients affected with gLEs have brain white matter defects that can be seen in MRI and exhibit variable neurologic phenotypes including motor impairment, hypotonia, pyramidal dysfunction, dystonia and/or dyskinesias, ataxia, seizures, cortical blindness, optic atrophy, and impaired cognitive development. The exact causes in half of gLEs are unknown. We studied three unrelated families affected with an undiagnosed gLE and discovered a homozygous germline mutation c.2536T>G in VPS11 by whole exome sequencing, a gene involved in membrane trafficking and fusion of the lysosomes and endosomes, as a novel cause of a new gLE syndrome.

  Study EGAS00001001767

• UK10K_NEURO_ASD_FI

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.These samples are a subset of a nationwide collection of Finnish autism spectrum disorder (ASD) samples. The samples have been collected from Central Hospitals across Finland in collaboration with the University of Helsinki. The samples consist of 93 individuals with a diagnosis of autistic disorder or Asperger syndrome from 36 families with at least two affected individuals. Of these individuals, 16 can be genealogically connected to form two large pedigrees originating from Central Finland, suggesting possible genetic risk factors shared identical by descent within the pedigrees. All diagnoses are based on ICD-10 and DSM-IV diagnostic criteria for ASDs. Additional phenotypic data is available for a subset of the individuals.For further information with regard to this cohort please contact Aarno Palotie (Aarno.palotie@helsinki.fi).

  Study EGAS00001000110

• UK10K NEURO ASD GALLAGHER

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This is an Irish sample set of individuals with ASD (approximately 50% with comorbid intellectual disability). Individuals have been diagnosed with ADI/ ADOS, measures of cognition/ adaptive function. They represent a more severe, narrowly defined cohort of ASD subjects. Family histories are available for some with measures of broader phenotype. For further information on this cohort please contact Nadia Bolshakova (bolshakn@tcd.ie).

  Study EGAS00001000112