3967 results for "*geneti*"

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• Human islet 3D chromatin maps provide insights into type 2 diabetes

  The transcriptional output of each cell type is controlled by thousands of enhancers, many of which contain genetic risk variants for common diseases such as type 2 diabetes (T2D). To gain insight into how enhancer variation influences diabetes risk, we created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated islet enhancers with their target genes, often located hundreds of kilobases away. We identified hubs that show spatial and functional connections between enhancersand target genes related to islet function and diabetes. We demonstrate that genetic variants distributed across hub enhancers have a major impact on T2D heritability, and use this knowledge to identify individuals in whom islet regulatory variation has a prominent role in T2D risk. Our results demonstrate the importance of 3D chromatin architecture for molecular interpretation of T2D genetic association signals, and define genomic spaces that harbor a distinct component of the T2D polygenic burden.

  Study EGAS00001002917

• Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

  follicular lymphoma (FL), the most common indolent non-Hodgkin’s lymphoma, remains incurable. A well-recognized complication of FL is its transformation to a diffuse large B-cell lymphoma (DLBCL)-morphology in a subset of patients, for which the clinical outcomes are poor. Recent genetic profiling and single case studies of donor-derived FL following stem cell transplantation had alluded to the putative existence of a ‘long lived’ tumor-initiating progenitor cell compartment from which successive disease events occurred. To chronicle the genetic changes associated with progression to transformation, we conducted whole-genome sequencing (WGS) of FL-tFL pairs and matched germline (GL) samples from six patients, a total of 20 genomes.

  Study EGAS00001000399

• Indonesian Genome Diversity Project

  Indonesia, the world’s fourth largest country by population, comprises an archipelago of about 900 permanently inhabited islands in tropical Asia, and hosts an astonishing array of human diversity that remains largely underrepresented in modern biological surveys. The region is unique for its key role in both the early and recent evolution of Homo outside of Africa. It has one of the first traces of anatomically modern humans in Eurasia, and was the focus of extensive interaction between archaic hominins and humans – both in the likely co-existence of H. floresiensis with modern humans, and in the introgression of Denisovans into the ancestors of its present inhabitants. More recently, Indonesia was a center of the spread of Neolithic culture by Austronesian speakers. Advancing maritime technologies allowed farming populations to treat this region as a springboard to reach oceanic islands as remote as Madagascar, Hawaii, Easter Island and New Zealand. Here we present complete human genomes from healthy individuals from multiple key islands in Indonesia and Papua. The genomes were sequenced to high depth (30x). The purpose of this dataset is to address different questions of human evolution in Island Southeast Asia and beyond, including early settlement of the area by anatomically modern humans, population structure, genetic admixture and adaptation, and contacts with archaic hominins. We employed a sampling strategy to capture a broad range of diversity across the region incorporating an average of 12 samples from each of 14 islands spanning Indonesia and Papua, from Sumatra in the west to New Britain in the east. Genomes from this dataset form part of an ongoing project to describe and understand human evolutionary history in Island Southeast Asia and Eurasia in general.

  Study EGAS00001003054

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003138

• High Altitude Pulmonary Hypertension

  The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls.

  Study EGAS00001003171

• Whole genome shotgun sequencing and somatic mutations data in Hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy.

  Study EGAS00001002578

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - WXS

  B-PLL is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003275

• Pancreatic cancer organoids recapitulate disease and allow personalized drug screening

  We report derivation of 30 Patient-Derived Organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical for pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic. The PRMT5 inhibitor EZP015556, shown to target MTAP negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP+ tumors. Taken together, the work presented here provides a platform to identify novel therapeutics to target pancreatic tumor cells using PDOs.

  Study EGAS00001003369

• Mutational patterns and regulatory networks in epigenetic subgroups of meningioma (H033)

  DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign-1, 2, 3, intermediate-A, B and malignant. Here, we set out to identify subgroup-specific mutational patterns and pathway regulation. Whole-genome-sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic and 22 radiation-induced (Mrad) meningiomas. RNA sequencing was added for 18 cases and chromatin-immunoprecipitation for the enhancer mark H3K27ac followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural alterations were found to contribute to the spectrum of mechanisms inactivating NF2 in sporadic meningioma similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3 was detected in both sporadic meningioma and Mrad, but distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. In general, the malignant MC presented a significantly higher exposure to AC3 and higher genomic instability beyond the mutational load than the other MCs. Pathway analysis of the ChIP-seq clusters revealed that the FOXM1 is most differentially activated in high-grade cases, along with super enhancer recruitment near HOX genes and respective upregulation of expression. This data further elucidate the biological mechanisms differentiating meningiomas of different WHO grade and epigenetic subgroups and suggest leveraging the genomic instability as novel therapeutic targets.

  Study EGAS00001003481

• A_study_of_the_molecular_pathogenesis_of_Splenic_Marginal_Zone_and_Diffuse_Large_B_Cell_Lymphoma

  We will perform exome sequencing on selected cases of splenic marginal zone lymphoma (SMZL) and diffuse large B-cell lymphoma (DLBCL) in order to characterise their genetic makeup and identify biomarkers for prognosis and prediction of treatment response.

  Study EGAS00001000335

• Pediatric Whole Genome Sequencing Diagnostic Utility

  The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. We compared diagnostic rate of WGS to CMA and targeted gene testing of 100 patients referred to The Hospital for Sick Children Genetics clinic in 2014. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In an additional 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling.

  Study EGAS00001001623

• Indonesian methylation data

  DNA methylation data were collected to study patterns of functional variation across the broad geography of Indonesia. The region has extremely diverse populations, with very different demographic histories and multiple genetic ancestries. This dataset reports Illumina Epic methylation chip data for individuals from three islands spanning this geographical region: Mentawai, Sumba and West Papua.

  Study EGAS00001003653

• Genetic landscape of pediatric ependymoma

  We performed whole-genome sequencing of 42 paired tumor/normal EPD genomes and analyzed somatically acquired single nucleotide variations (SNVs), insertion/deletions, structural variations and copy number variations in the cancer genomes

  Study EGAS00001000254

• Genomic and epigenomic characterization of juvenile myelomonocytic leukemia (JMML)

  Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. While some cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients, however, the 5-year event-free survival reaches only about 50%. Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by genetic alterations in CBL, KRAS, NF1, NRAS, or PTPN11 in about 90% of patients. So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. As a consequence, established clinical and genetic markers fail to fully represent the observed disease heterogeneity. We hypothesized that DNA methylation profiling, either alone or in combination with genetic alterations, might provide a molecular basis for disease classification. Genome wide DNA methylation analysis using the HumanMethylation450 Bead Chip array was performed in a discovery cohort of 20 patients (19 JMML, 1 Noonan syndrome). The clinical relevance of our findings was assessed in an unselected sample set consisting of 147 consecutive patients with JMML (n=129) or Noonan syndrome (n=18) associated myeloproliferative disorder (n=18) registered in the EWOG-MDS 1998 & 2006 trials. Data integration was performed in a subset of patients with available exome sequencing (n=50) and expression profiling (n=15) data. This integrated approach identified three JMML subgroups characterized by distinct clinical and biological features. This analysis further suggested a molecular mechanism by which additional genetic events, presumably further activating the RAS-RAF-MEK-ERK pathway, mediate DNA hypermethylation via up-regulation of DNMTs in more aggressive JMML cases.

  Study EGAS00001002511

• Evolutionary Origins of Recurrent Pancreatic Cancer

  Surgery is the only curative option for patients with Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and their matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease develops from a monophyletic or polyphyletic origin, and this distinction has potential clinical relevance. In all patients, treatment induced genetic bottlenecks led to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings strongly advocate for routine post-treatment sampling in the management of recurrent pancreatic cancer.

  Study EGAS00001004097

• CD8+ T-cell exhaustion induced by leukemic cells drives progression in Chronic Lymphocytic Leukemia

  In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological landscapes. For that, we analyzed paired samples obtained from CLL patients at diagnosis and progression before front-line treatment or at diagnosis and long-term asymptomatic follow-up. By whole-exome sequencing (WES), we found that CLL cells displayed limited genetic evolution at progression. Conversely, T cells from progressing patients showed significant immunophenotypical and transcriptional changes over time not observed in patients that did not progress. Specifically, we found that CD8+ T cells at progression were characterized by an increasing terminally exhausted effector phenotype (T-betdim/- Eomeshi PD1hi) with high co-expression of inhibitory receptors (PD1, CD244 and CD160). This exhausted status in CD8+ T cells was induced by progressing leukemic cells mainly through a mechanism dependent on soluble factors, including IL-10. Thus, we demonstrate that immunological changes are of paramount importance for CLL clinical progression, thereby providing a rationale for the use of early immunotherapeutic intervention in this disease.

  Study EGAS00001004116

• Canadian Prostate Cancer Genome Network

  Over 5 years, CPC-GENE will sequence the genomes of 350 intermediate risk prostate cancers to identify genetic signatures that differ in cancers that responded well to treatment compared with those that did not. CPC-GENE will also sequence multiple regions of prostate cancer from the same gland to determine if and how the genetic make-up of prostate cancer varies within an individual man’s prostate

  Study EGAS00001000900

• Inherited damaging mutations in immune-related genes favour the development of genetically heterogeneous synchronous colorectal cancer.

  Synchronous colorectal cancers are physically separated tumours that develop simultaneously in the intestine. To understand how common genetic and environmental backgrounds influence the development of multiple tumours, we conduct a genome-wide comparative analysis of somatic alterations of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire discordant somatic alterations, and follow different clonal developments.

  Study EGAS00001001461

• Whole exome sequencing of Parkinson's disease patients from the United Kingdom

  As part of the International Parkinson's Disease Genomics Consortium, exomes of Parkinson's disease (PD) patients and healthy controls were sequenced to study the genetic etiology of PD. This UK cohort consists of 70 PD patients. Researchers can apply for access to fastq, vcf and binary plink files for this cohort.

  Study EGAS00001002156

• Whole_genome_sequencing_in_a_multiplex_Crohn_s_disease_family

  In 2009 we identified a four-generation family with over 700 members and 41 affected with Crohn's disease (CD). At the time we sequenced the exome of 6 affected individuals but did not identify any coding variants which appear to explain the high prevalence of disease. Since then we have collected DNA from a large number of additional family members, genotyped linkage arrays on the entire family to refine genomic regions shared by identity by descent and genotyped affected and unaffected members at known CD risk loci identified by Genome Wide Association Studies (GWAS). These analyses have confirmed that a significant unexplained excess of disease remains after accounting for all known genetic factors, and that several regions of the genome are shared by a large fraction of affected individuals. We therefore perform whole genomes sequencing from 8 individuals which will allow us to impute the complete sequence of nearly all the members of the two largest and most severely affected branches of the family.

  Study EGAS00001000060

• HipSci HumanExome BeadChip analysis - monogenic diabetes

  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 monogenic diabetes.

  Study EGAS00001001273

• HipSci_RNASEQ_Battens

  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 perform RNAseq on iPS lines from Battens patients.

  Study EGAS00001001987

• HipSci_RNASEQ_Ataxia

  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 perform RNAseq on iPS lines from hereditary cerebral ataxia patients.

  Study EGAS00001001992

• T2D-GENES: Exome sequencing

  The Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) is a large collaboration effort between the University of Michigan, Broad Institute, the Wellcome Trust Centre for Human Genetics, University of Chicago, NIDDK, Texas Biomedical Research Institute, University of Texas Health Science Center, University of North Carolina, Blood Systems Research Institute, and University of Mississippi Medical Center. The goal of this study is to identify genetic variants for type 2 diabetes through multiethnic sequencing studies. In this study, we use next generation sequencing to assess the role of common, low frequency, and rare variants on type 2 diabetes risk. We preformed exome sequencing in 6,546 T2D cases and 6,457 control individuals of multiethnic origin, including individuals of African American, East Asian, South Asian, Hispanic, and European descent.

  Study EGAS00001001460

• HipSci_RNASEQ_BPD

  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 perform RNAseq on iPS lines from Blood platelet disorders patients.

  Study EGAS00001001993

• HipSci_RNASEQ_Hypertrophic_Cardiomyopathy

  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 perform RNAseq on iPS lines from Hypertrophic Cardiomyopathy patients.

  Study EGAS00001001994

• TRACERx 100: metastatic samples

  Whole exome sequencing of 10 metastatic biopsies from four TRACERx100 patients (see EGA dataset EGAS00001002247), collected either after relapse or death. The data from these samples are initially published with Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature http://dx.doi.org/10.1038/nature22364 (2017). Abstract: Earlier detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a patient-specific approach to ctDNA profiling in the first 100 lung TRACERx (TRAcking Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release in early-stage non-small cell lung cancer and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies.

  Study EGAS00001002415

• HipSci___Whole_Exome_sequencing___Cardiomyopathy

  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 perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with hypertrophic cardiomyopathy

  Study EGAS00001001980

• HipSci_RNASEQ_Congenital_hyperinsulinia

  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 perform RNAseq on iPS lines from Congenital hyperinsulinia patients.

  Study EGAS00001001988

• HipSci_RNASEQ_Macular_Dystrophy

  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 perform RNAseq on iPS lines from Macular Dystrophy patients

  Study EGAS00001001995

• Distinct portrayal of lesions in synchronous multifocal lung adenocarcinoma revealed by genome sequencing

  Distinguishing multiple primary lung cancers in the synchronous multifocal intrapulmonary lesions has important significance on clinical staging and therapeutic decision. To investigate genomic aberration profiles, we applied whole genome and whole exome sequencing, and microarray-based comparative genomic hybridization on 15 intrapulmonary tumors derived from six patients with synchronous multifocal lung cancers having similar histological diagnosis. Any pair of intrapulmonary tumors in a single patient, which shared the identical genetic background and environment, showed an extinctive heterogeneity between each other. Phylogenetic relationship analysis indicated an independently branched evolution among all the tumors, suggesting they were multiple primary lung cancers. EGFR or KRAS mutations were found in 7 or 3 out of the 15 tumors, from 3 or 2 patients, respectively. Somatic mutational heterogeneity of these two genes in a single patient was also observed. Our analysis indicates genomic aberration profiling is valuable for identification of multiple primary lung cancer, especially when high histopathological concordance was observed between lesions. We also suggest a thoroughly molecular diagnosis against therapeutic target genes should be taken for each accessible nodule before making a plan for adjuvant therapy.

  Study EGAS00001001572

• Whole-exome sequencing of breast cancer metastasis and corresponding blood samples

  This study included samples from metastatic breast cancer patients who underwent a biopsy in the context of SAFIR01 (NCT01414933), SAFIR02 (NCT02299999), SHIVA (NCT01771458) and MOSCATO (NCT01566019) prospective trials. These French multicentre trials used high throughput genome analysis on fresh frozen tumor biopsies as a therapeutic decision tool for metastatic cancer patients, with solid cancers (SHIVA, MOSCATO) or specifically with breast cancer (SAFIR01, SAFIR02). All patients gave their informed consent for translational research and genetic analyses of their somatic DNA. Overall, whole-exome sequencing for a total of 216 pairs of metastatic tumor and unmutated DNA derived from corresponding blood samples was performed using Illumina technology. The results of the analysis of the mutational profile of metastatic breast cancer was reported in Lefebvre et al. (PMID:28027327).

  Study EGAS00001001695

• Genetics_of_gene_expression_in_human_macrophage_response_to_Salmonella

  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 EGAS00001002236

• HipSci HumanExome BeadChip analysis - Macular Dystrophy

  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 Macular Dystrophy.

  Study EGAS00001002014

• WES analysis of a mixed cohort of pituitary tumors

  BACKGROUND: Sporadic pituitary adenomas are the second most common primary brain tumor, but their genetics remains incompletely understood. We performed deep DNA sequencing of 42 pituitary macroadenomas, including hormonally active and atypical adenomas. METHODS: Pituitary adenomas representative of a spectrum of histopathologic subtypes, primary and recurrent tumors, and MIB-1 proliferative indices were profiled. Whole-exome sequencing was performed on tumors and paired blood followed by analysis of somatic copy number alteration and mutation. RESULTS: On the whole, the tumors harbored a low rate of mutations, similar to other benign brain tumors. However, almost one-third (29%) exhibited somatic copy-number alterations across large fractions of the genome (up to 99%). Despite such widespread genomic disruption, these tumors had few focal events, which is atypical among highly-disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy-number alterations involving less than 6% of the genome. Among the highly-disrupted group, 92% were functional or atypical null-cell adenomas, whereas 87% of the less-disrupted group were clinically non-functional adenomas. The only significantly recurrent events were arm-level losses of chromosomes 1, 2, 11, and 18. No significantly recurrent mutations or insertion/deletion events were identified, suggesting no genes are altered by exomic mutations in >15% of pituitary tumors. CONCLUSIONS: Genomic characterization of a large series of sporadic pituitary adenomas reveals two classes of tumor, based on genomic disruption from arm-level copy-number alterations, which associate with hormonal and histologic subtypes.

  Study EGAS00001001714

• Reconstructing the dispersals and adaptive history of Bantu-speaking populations in Africa and North America

  Bantu languages are spoken by ~310 million Africans, yet the genetic history of Bantu-speaking populations remains largely unexplored. We generated genomic data for 1,318 individuals from 35 populations in western central Africa, where Bantu languages originated. We found that early Bantu speakers first moved southward, through the equatorial rainforest, before spreading toward eastern and southern Africa. We also found that genetic adaptation of Bantu speakers was facilitated by admixture with autochthonous populations, particularly for the HLA and LCT loci. Finally, we identified a major contribution of western central African Bantu speakers to the ancestry of African Americans, whose genomes present no strong signals of natural selection. Together, these results highlight the contribution of Bantu-speaking peoples to the complex genetic history of Africans and African Americans.

  Study EGAS00001002078

• RNA-sequencing data from 195 B-cell precursor acute lymphoblastic leukemias and mate pair whole genome sequencing data from 15 B-cell precursor acute lymphoblastic leukemias

  Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). Using RNA-sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a new subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene expression profile and coexisting ETV6 and IKZF1 alterations. Taken together, this study provides a detailed overview of fusion genes in pediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide novel therapeutic options in this disease.

  Study EGAS00001001795

• Sequencing of pancreatic cancer primary tumors and metastases

  The extent of heterogeneity of driver gene mutations present in naturally occurring metastases is largely unknown, i.e. treatment-naïve metastatic disease. To address this issue, 60x whole genome sequencing of 26 metastases from 4 patients was carried out. We found that the identical driver gene mutations were present in every metastatic lesion of each patient studied. Passenger gene mutations not known or predicted to have functional consequences accounted for all intratumoral heterogeneity. Even with respect to these passenger gene mutations, the genetic similarity among the founding cells of metastases was markedly higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of driver gene mutations among metastases in the same patient has critical, encouraging implications for the success of future targeted therapies in advanced stage disease.

  Study EGAS00001002186

• IDENTIFICATION AND TARGETED MANAGEMENT OF A PATIENT WITH A NEURODEGENERATIVE DISORDER CAUSED BY BIALLELIC MUTATIONS IN SLC5A6

  We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood-brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate and lipoate) replacement therapy.

  Study EGAS00001003861

• Investigating genetic susceptibility to rheumatic heart disease in Oceania

  This case-control study investigated susceptibility to rheumatic heart disease in over 3,000 individuals recruited across eight Oceanian countries. Cases were patients with rheumatic heart disease and controls were members of the general population. In addition to the Illumina HumanCore-24 BeadChip genotyping, a subset of 128 samples were analysed using the higher density Illumina HumanOmniExpressExome BeadChip of which 64 were also analysed using low coverage sequencing with the Illumina HiSeq 4000 platform.

  Study EGAS00001001881

• Resolving_the_Genetic_Architecture_of_Aseptic_Loosening_After_Total_Hip_Replacement

  This is a genome-wide association scan of aseptic loosening after total hip replacement in a Norwegian population. 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001883

• The molecular landscape of colorectal cancer reveals genetic mutations.

  We performed whole-exome sequencing of tumor samples and adjacent normal mucosae from 46 patients to characterize the genetic alterations in China.

  Study EGAS00001001893

• HER2_positive_Breast_Cancer_

  We propose to definitively characterise the somatic genetics of HER2+ve breast cancer through generation of comprehensive catalogues of somatic mutations in a number of cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Study EGAS00001000042

• PCGP Ph-like ALL

  Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted

  Study EGAS00001000654

• HipSci_RNASEQ_Alport

  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 perform RNAseq on iPS lines from Alport syndrome patients.

  Study EGAS00001001986

• HipSci___Whole_Exome_sequencing___Alport

  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 perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Alport syndrome

  Study EGAS00001001974

• HipSci_RNASEQ_PID

  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 perform RNAseq on iPS lines from Platelet and bleeding disorders patients

  Study EGAS00001001990

• Measuring the level of relatedness between NGS datasets

  Sequencing technologies are providing increasingly detailed insight in genetic makeup are paving their way into molecular diagnostics. The field will benefit from rigorous and bias-free measures for the quality of sequence data and for the proper representation of the complexity of the original samples. While current methodologies rely on the availability of a well-characterized reference genome, we propose kMer profiling for alignment-free assessment of the quality, comparability, and complexity of sequencing datasets. We show that kMer detects technical artefacts such as high duplication rates, library chimaeras, and differences in library preparation protocols in whole-genome, whole-exome, and RNA sequencing data. Additionally, it successfully captures the complexity and diversity of microbiomes. Thus, kMer allows for a robust evaluation of the quality and complexity of sequencing data without relying on any prior information and opens the way to a more reliable biological reasoning.

  Study EGAS00001000600

• Genomic_profiling_of_B_other_Adult_ALL_WGS

  Adult ALL is an aggressive leukaemia, affecting adults of all ages. It is associated with a rapid onset and poor outcomes. Our understanding of adult ALL genome has been limited to molecular markers first described in paediatric ALL and validated in adult ALL and to date there have been no studies investigating the genomics of Adult ALL. We will perform whole genome sequencing on at least 100 Adult ALL cases. Priority will be given on ALL cases without a known primary lesion by cytogenetic analysis which are categorised as “B-other”. We will also sequence representative cases of each known subtype. This will deliver a comprehensive annotation of the genomic landscape of Adult ALL to include acquired somatic mutations (substitutions, indels, structural variants/fusion genes) and copy number profiles. The focus on B-other Adult ALL is likely to result in new and previously undescribed genomic lesions.

  Study EGAS00001002474

• HipSci HumanHT 12 Expression BeadChip analysis - Retinitis Pigmentosa

  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 Retinitis Pigmentosa.

  Study EGAS00001002030