3906 results for "*geneti*"

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• Sequencing data for ICGC Oesophageal Adenocarcinoma tissue samples - 129_cohort

  Sequencing data for ICGC Oesophageal Adenocarcinoma tissue samples - 129_cohort EAC whole genomic sequencing data - Publication Secrier & Li et al., 2016, Nature Genetics

  Dataset EGAD00001002218

• Autozygosity pilot - British-Pakistani from Birmingham 2

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing British-Pakistani cohort samples from Birmingham will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consists of low coverage whole exome sequencing on these samples.

  Dataset EGAD00001001026

• Constitutional and somatic genomic rearrangements coherently restructure chromosome 21 in acute lymphoblastic leukaemia

  Changes in gene dosage are a major driver of cancer1, engineered from a finite, but increasingly well annotated, repertoire of mutational mechanisms2-6. These processes operate over levels ranging from individual exons to whole chromosomes, often generating correlated copy number alterations across hundreds of linked genes. An example of the latter is the 2% of childhood acute lymphoblastic leukemia (ALL) characterized by recurrent intrachromosomal amplification of megabase regions of chromosome 21 (iAMP21)7,8 To dissect the interplay between mutational processes and selection on this scale, we used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. We find that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have ~2700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by chromothripsis involving both sister chromatids of the dicentric Robertsonian chromosome. In contrast, sporadic iAMP21 is typically initiated by breakage-fusion-bridge (BFB) events, often followed by chromothripsis or other rearrangements. In both sporadic and iAMP21 in rob(15;21)c individuals, the final stages of amplification frequently involve large-scale duplications of the abnormal chromosome. The end-product is a derivative chromosome 21 or a derivative originating from the rob(15;21)c chromosome, der(15;21), respectively, with gene dosage optimised for leukemic potential, showing constrained copy number levels over multiple linked genes. In summary, the constitutional translocation, rob(15;21)c, predisposes to leukemia through a novel mechanism, namely a propensity to undergo chromothripsis, likely related to its dicentric nature. More generally, our data illustrate that several cancer-specific mutational processes, applied sequentially, can co-ordinate to fashion copy number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

  Dataset EGAD00001000658

• Multi-omics analysis defines core genomic alterationsin pheochromocytomas and paragangliomas

  Pheochromocytomas and paragangliomas (PCC/PGL) are neural crest derived tumors with a very strong genetic component. We report the first integrated genomic portrayal of a large collection of PCC/PGL. SNP array analysis revealed distinct copy-number patterns associated with genetic background. Whole-exome sequencing showed a low mutation rate of 0.3 mutations per megabase, with few recurrent somatic mutations in genes not previously associated with PCC/PGL. DNA methylation arrays and miRNA sequencing identified DNA methylation changes and miRNA expression clusters strongly associated with mRNA expression profiling. Overexpression of the miRNA cluster 182/96/183 was specific of SDHB-mutated tumors and induced invasive traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster appeared as a potential driver in a subgroup of sporadic tumors. Altogether, the complete genomic landscape of PCC/PGL is mainly driven by distinct germline and/or somatic mutations in susceptibility genes and reveals different molecular entities, characterized by a set of unique genomic alterations.

  Dataset EGAD00001000986

• Metastatic Breast Cancer Whole Genome

  We propose to definitively characterise the somatic genetics of Metastatic breast cancer through generation of comprehensive catalogues of somatic mutations in Metastatic breast cancer cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Dataset EGAD00001000899

• Genetic background for cardio vascular disorders in the general Finnish population

  Low coverage (4-6x) sequencing on samples from population cohorts (Finrisk, Health2000) will be done at Wellcome Trust Sanger Institute (WTSI) using Illumina HiSeq sequencing technology. We will produce 100bp paired end reads. Variants will be called using the 1000 Genomes Project pipeline. The samples have been selected from a national representative set of approximately 30,300 samples and comprises 500 individuals of each gender in the extreme tail of high density lipoprotein (HDL) concentrations. Included individuals were between 25 and 65 years of age. Individuals with a diagnosis of diabetes or BMI>30 were excluded from the study.

  Dataset EGAD00001001251

• Autozygosity pilot - British-Pakistani from Birmingham

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 50-80%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing British-Pakistani cohort samples from Birmingham will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consist of low coverage whole exome sequencing on these samples.

  Dataset EGAD00001001025

• Mechanisms of patient response to Dabrafenib in Melanoma

  Samples will be from the BRF113683 (BREAK-3) study which is a Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma (n=250 enrolled)*NGS [Agilent capture (Sanger V2 panel): 360 genes and 20 gene fusions; Illumina HiSEQ Sequencing]*CNV: [via NGS or Affy SNP 6.0 or Illumina Omni (TBD)]Bioinformatics: Analysis will be performed using core Sanger informatics pipelines similar to those previously described (Papaemmanuil E et al. (2013) Blood. 22:3616 -3627). Briefly, copy number analysis will be performed using the ASCAT algorithm, and base substitutions, small insertions and deletions using the CAVEMAN and Pindel algorithms, respectively. Statistical approaches including generalized linear models will be used to predict clinical variables such as maximum clinical response and duration of response using genetic data. Sanger and EBI to conduct analysis; Raw data and correlation with clinical endpoints to be analyzed by both EBI/Sanger and GSK (unique pipeline analyses to increase call confidence)

  Dataset EGAD00001001375

• MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

  Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long non-coding RNAs (lncRNAs), on the way MYC is able to influence cellular transcriptome. To this aim we have intersected RNA-sequencing data from two MYC-inducible cell lines and from a cohort of 91 mature B-cell lymphomas carrying, or not carrying, genetic variants resulting in MYC over-expression. By this approach, we identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them we focused on a lncRNA that we named MINCR, for MYC-Induced long Non-Coding RNA, showing a strong correlation with MYC expression in MYC-positive lymphomas and also in pancreatic ductal adenocarcinomas. To understand its cellular role we performed RNA interference (RNAi) experiments and found that MINCR knock-down is associated with a reduction in cellular viability, due to an impairment in cell cycle progression. Differential gene expression analysis following RNAi showed a strongly significant enrichment of cell cycle genes among the genes down-regulate following MINCR knock-down. Interestingly these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of MYC transcriptional program. Accordingly, following MINCR knock-down, we observed a reduction in the binding of MYC to the promoters of selected cell cycle genes. Finally we provide evidences that down-regulation of AURKA, AURKB and CTD1 may explain the reduction in cellular proliferation observed upon MINCR knock-down. We therefore suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.

  Dataset EGAD00001001441

• 33 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS)

  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.

  Dataset EGAD00001001901