3994 results for "*geneti*"

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• Second hit rare genetic variants in families with seemingly GBA gene associated Parkinson’s disease

  Study EGAS00001004777

• HipSci HumanExome BeadChip analysis - Primary immune deficiency

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Primary immune deficiency.

  Study EGAS00001002012

• BLUEPRINT DNA Methylation 450K data of mantle cell lymphoma

  We have applied an analytic strategy to decipher the DNA methylome of 86 mantle cell lymphomas (MCL) in light of the methylome of the entire B-cell lineage. In this way, we first identified two MCL subgroups that respectively carry epigenetic imprints of pre- and post-germinal center B cells. Secondly, we observed that pure tumor-specific changes are rare, as most (89-99%) DNA methylation alterations in MCL are within or in close proximity of those regions showing dynamic methylation in normal B cells. Several thousand of these differentially methylated regions in MCL show concurrent changes in enhancer-associated histone modifications, including a region located 650 Kb away from the MCL oncogene SOX11. At the clinical level, epigenetic and genetic changes co-evolve during MCL progression and the magnitude of epigenetic changes is associated with overall survival of the patients.

  Study EGAS00001001637

• BLUEPRINT Epigenetic characterization of megakaryocytes and erythroblasts

  Megakaryocytes and erythroblasts derive from the same progenitor cell type but carry out very different functions. In order to understand how the different functional phenotypes arise we have characterised the epigenetic landscape of these cells.

  Study EGAS00001001641

• HipSci HumanHT 12 Expression BeadChip analysis - Hereditary Cerebellar Ataxias

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Hereditary Cerebellar Ataxias.

  Study EGAS00001002020

• 33 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) had whole exome sequencing performed. Cells were sorted by FACSAria using CD138, CD19 and CD56 to obtain a pure abnormal plasma cell population. Generated somatic variants were compared to a previous study of 463 multiple myeloma patients.

  Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma (MM) with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about molecular mechanism of malignant transformation. We have performed whole exome sequencing together with SNP array analysis in 33 flow-cytometry separated abnormal PC samples of MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations (NS-SNVs) and copy number alterations (CNAs) were present in 97.0% and in 63.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in MGUS compared to MM (p<10-4) and we have identified 6 myeloma significantly mutated genes which are KRAS, NRAS, DIS3, HIST1H1E, EGR1 and LTB in the MGUS dataset. We also found a positive correlation with increasing chromosome changes and somatic mutations. IGH translocations were present in 27.3% of cases comprising t(4;14), t(11;14), t(14;16) or t(14;20) and were in a similar frequency to MM, which corresponded with primary lesion hypothesis. Data from this study showed MGUS is a genetically comprehensive disease, however overall genetic instability is significantly lower compared to MM.

  Study EGAS00001001658

• Investigating_the_genetics_of_immunity_against_Salmonella_in_humans

  This study entails whole genome sequencing of an interleukin (IL)-12 b-1 receptor-deficient individual who presented with a chronic systemic Salmonella Enteritidis infection that did not resolve with standard IFNg and antibiotic treatment. Whole genome sequencing of the patient’s parents are also included.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 EGAS00001001664

• Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase III clinical trial

  The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase III PETHEMA-FLUGAZA clinical trial, that randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine or induction and consolidation with 5-azacitidine. After consolidation, patients continued treatment if MRD≥0.01% or stopped if MRD<0.01%, assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N=72) was the only independent prognostic factor for cumulative-incidence of relapse (HR:2.95;P=.002) and relapse-free survival (HR:3.45;P=.002). A trend for longer overall survival was observed in patients with undetectable MRD (N=13/72). Although leukemic cells from most elderly AML patients display phenotypic aberrancies vs their normal counterpart (N=258/265), CD34 progenitors from cases with undetectable MRD by MFC displayed extensive genetic abnormalities identified by whole-exome sequencing. This study supports MRD assessment to refine CR after semi-intensive therapy or hypomethylating agents, but unveils that improved sensitivity is warranted to individualize treatment and prolong survival of elderly AML patients achieving undetectable MRD.

  Study EGAS00001004574

• Histological Transformation and Progression in Follicular Lymphoma: a Clonal Evolution Study

  Background: Follicular lymphoma (FL) is an indolent, yet incurable B-cell malignancy. A subset of patients experience increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immuno-chemotherapy. The nature of tumor clonal dynamics leading to these clinical endpoints is poorly understood and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the timecourse of FL clinical histories. Methods and Findings: Using a combination of whole genome sequencing, targeted deep sequencing and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in n=15 transformation patients and n=6 progressors, and measured their change in abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimen. This pattern was independent of time to transformation and treatment modality. By contrast, progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immuno-chemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in a validation cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical endpoints. We found 12 genes were more commonly mutated in transformed samples than in preceding FL, including TP53, B2M, CCND3, GNA13, S1PR2 and P2RY8. Moreover, 10 genes were more commonly mutated in diagnostic specimens of early progressors including TP53, BTG1, MKI67 and XBP1. Conclusions: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implication for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

  Study EGAS00001001709

• ENU_NCI_H508_cetuximab_fixed_concentration_project

  Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC

  Study EGAS00001001744