Search Results - EGA European Genome-Phenome Archive

Breast Cancer - Very young women

This project will focus on sequencing of breast cancer from young age cancer patients characterized by age at diagnosis under 35. Based on the incidence rate by Korean National Cancer Incidence Database, breast cancer is the most common solid tumors among young adults aged 15-34 excepting thyroid cancer (Cancer statistics in Korea (2012)). This project just started from the mid of 2015. National cancer center in Korea are collecting more than 100 tumor specimens from breast cancer patients aged 20-34. Genetic features of young patients will be investigated with somatic mutation pattern, structural variations, and canonical pathways.

Study EGAS00001001908

The genetic structure of Norway

The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway’s long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been the most isolated region in Norway, highlighting the open sea as a barrier to gene flow into Norway.

Study EGAS00001004826

Location specific ACVR1, FGFR1 and TP53 mutations in pediatric glioblastomas in conjunction with H3.3 K27M.

Recurrent somatic H3 K27M mutations characterize midline pediatric high-grade astrocytomas (pHGAs). In 40 treatment-naïve midline pHGAs we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with H3.1K27M, while FGFR1 mutations/fusions occur in thalamic tumors in conjunction with H3.3 K27M. Genetic profiles of pHGA show actionable targets, suggesting that pre-treatment biopsy could effectively orient therapeutic efforts.

Study EGAS00001000720

HipSci___Whole_Exome_sequencing___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 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 blood and platelet disorders

Study EGAS00001001976

DNA methylomes of monozygotic twins clinically discordant for multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although genetic susceptibility is important, a modest concordance rate for MS in monozygotic (MZ) twins suggests that interaction with other risk factors is required to develop clinical symptoms. In this study, we examined whether DNA methylation differences contribute to the discordant clinical manifestation of MS in MZ twins, and studied the impact of MS treatments on the DNA methylome. Genome-wide DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) of 45 MZ twins clinically discordant for MS were generated using the Illumina HumanMethylationEPIC array. Repetitive element methylation and selected differentially methylated positions (DMPs) were validated using targeted deep bisulfite sequencing (TDBS). In addition, we performed whole genome bisulfite sequencing (WGBS) to profile CD4+ memory T-cells of a subset of four MS discordant MZ twins. Our results show that interferon treatment causes robust DNA methylation changes and several epigenetic biomarkers for interferon treatment response were identified. However, overall the PBMC-based methylomes of the MS discordant MZ twins were highly similar, since large systematic methylation differences (>5%) were absent in the data. This suggests that previously reported large methylation changes are probably caused by genetic rather than epigenetic differences. In addition, our data does not support the hypothesis that the observed maternal parent-of-origin effect in MS is due to genomic imprinting errors, and no evidence was found that copy number variations explain the discordant phenotype in these MZ twins. Although not genome-wide significant, a couple of DMPs associated with the MS phenotype were identified and successfully technically replicated using TDBS, including a differentially methylated region (DMR) in the promoter of the transmembrane protein encoding gene TMEM232. Another MS-associated DMP, located in an enhancer in the gene body of the transcription factor ZBTB16, was also associated with medium-term glucocorticoid treatment history. WGBS analysis confirmed this DMP as a promising epigenetic biomarker for glucocorticoid treatment. In conclusion, this epigenome-wide association study (EWAS) in genetically identical twins identified a DMR in the TMEM232 promoter as a candidate loci associated with the clinical manifestation of MS. In addition, epigenetic biomarkers for MS treatments were identified, revealing that not only short-term, but also medium-term treatment effects are detectable in immune cells, which should be taken into account in future EWAS designs.

Study EGAS00001003147

Sequencing of heritable Bleeding and Platelet Disorders

The BRIDGE-BPD study aims to discover new causal genes for Bleeding and Platelet Disorders (BPD) by high throughput sequencing using cluster analyses based on improved and standardized deep phenotyping of cases. BPD is one of the 13 Rare Disease projects under the NIHR BioResource Rare Diseases BRIDGE consortium, which is a collaboration aiming to discover the genetic sequence variants underlying unresolved inherited disorders and to improve identification of already identified high penetrance variants.

Study EGAS00001001172

HipSci HumanExome 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 Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Hereditary Cerebellar Ataxias.

Study EGAS00001002005

HipSci HumanHT 12 Expression BeadChip analysis - Kabuki syndrome

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 Kabuki syndrome.

Study EGAS00001002022

Genome-wide DNA-methylation assessment by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison

DNA-methylation is an important epigenetic feature in health and disease. Two cost-efficient genome-scale methodologies to assess DNA-methylation are MethylCap-seq and Illumina's Infinium HumanMethylation450 BeadChips (HM450). However, objective information regarding the best-suited methodology for a specific research question is scant. Therefore, we performed a large-scale evaluation on a set of 70 brain tissue samples obtained from 65 glioblastoma and 5 non-tumoral brain tissues, using a gold standard free Bayesian modeling procedure. While conditional specificity was adequate for both approaches, conditional sensitivity was systematically higher for HM450. Also the genome-wide characteristics were compared, revealing that the HM450 probes assess less than 10% of the regions identified as methylated by MethylCap-seq. Hence the latter method may detect more potentially relevant DNA-methylation, defined by either functional location or previously reported differentially methylated candidate regions. Our results therefore indicate that – at least for the tissue under study - both methodologies are complementary, with a higher sensitivity for HM450, but a far larger genome-wide coverage for MethylCap-seq. Note that here only the relevant MethylCap-seq data is deposited, for the HM450 data we refer to GEO (GSE60274).

Study EGAS00001001191

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

Illumina HumanCoreExome genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium (BSSH-GODD consortium) collection

Dupuytren's Disease (DD - OMIM126900) is the most common heritable disorder of connective tissue. It is a fibroproliferative disorder of the palmer fascia, causing flexion contractures of affected digits. DD affects men more commonly than women. DD is an archetypal complex disease, with multiple genetic and environmental factors affecting the final expression of the disease phenotype. The incidence increases with age, and the prevalence of DD is therefore increasing as the UK population ages. Half of all patients present before age 60. DD causes significant functional impairment, and severe contractures can lead to permanent disability. The mainstay of current treatment is surgery, but recurrence and complications are both high. For severe contractures, the only suitable treatment option is amputation. The direct costs to the NHS are high, and underestimate the true economic costs to society. We collected salivary samples from adults in the UK who have had surgery for DD. We have genotyped these samples using the Illumina HumanCoreExome Beadchips. https://research.ndorms.ox.ac.uk/public/dupuytrens/what-is-dupuytrens-disease/

Study EGAS00001001206

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy and is characterized by a striking degree of heterogeneity. We enrolled a total of 1001 DLBCL patients and comprehensively defined the landscape of genetic mutations, copy number alterations and expression through whole-exome and transcriptome sequencing. We identified 150 genetic drivers of DLBCL including many novel, clinically relevant genes (e.g. SPEN, SETD1B and KLHL14). Genetic drivers were highly enriched among essential genes identified by CRISPR screening in DLBCL cell lines including those of immediate potential therapeutic relevance such as MTOR, SYK, SF3B1 and XPO1. RHOA emerged as a critical driver gene from our genetic analysis and CRISPR screen; we further delineated its functional role in vitro and in vivo models to define its role as an essential oncogene in DLBCL. Our work thus identifies the functional landscape of genetic drivers and their clinical and therapeutic relevance in DLBCL patients.

Study EGAS00001002606

Genetic Basis of Hepatosplenic T Cell Lymphoma (HSTL)

Hepatosplenic T cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy number alterations in the disease. Chromatin modifying genes including SETD2, INO80 and ARID1B were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates novel gene mutations linked to HSTL pathogenesis and potential treatment targets.

Study EGAS00001002182

Molecular Signature of Saudi Thyroid Cancer Using whole exome sequencing

In Saudi Arabia, thyroid cancer ranked second only to breast cancer among females, eleventh among males and this increased incidence is prevalent in other Gulf Council Countries also. Differentiated thyroid cancer, which includes papillary thyroid cancer (PTC) and follicular subtypes, accounts for 90% of all thyroid malignancies. Currently, there are no clinical or molecular diagnostic tools to predict recurrence and aggressiveness of a subset of PTC. With the goal of better understanding the pathobiology of thyroid carcinogenesis we will use Whole Exome Sequencing to decipher the molecular and genetic signature of Saudi PTC based on International Cancer Genome Consortium (ICGC) Guidelines. The study will provide a better understanding of PTC and should have important clinical implications in the development of new and better strategies for targeted therapeutic intervention for the treatment of Saudi Arabian PTC

Study EGAS00001000680

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

Genetic_mechanisms_of_resistance_to_chemotherapy_in_breast_cancer

Resistance towards chemotherapy is one of the main causes of treatment failure and deathamong breast cancer patients.The main objective of this project is to identify genetic mechanisms causing some breastcancer patients not to respond to a particluar type of chemotherapy (epirubicin) while otherpatients respond very well to the same treatment.In the project we will perform genome / exome sequencing of a selection of breast cancerpatients (n=30). These patients are drawn from a cohort where all patients have recievedtreatment with epirubicin monotherapy before surgical removal of a locally advanced breasttumour, and where all patients have been subjected to objective evaluation of the response tothe therapy.Subsequent to sequencing, we will analyse the data and compare with the clinical data foreach patient (object response to therapy). The main aim being to identify mutations that areassociated with resistance to epirubicin.Identification of mutations with strong predictive value, may have a direct impact on cancertreatment since it opens the possibility for genetic testing of a tumour, and desicion on whichdrug is likely to work best, prior to treatment start.

Study EGAS00001000276

HipSci HumanExome BeadChip analysis - Kabuki syndrome

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 Kabuki syndrome.

Study EGAS00001002007

HipSci HumanExome BeadChip analysis - Alport Syndrome

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 Alport Syndrome.

Study EGAS00001002009

Breast_Cancer_Whole_Genome_Sequencing

We propose to definitively characterise the somatic genetics of ER+ve, HER2-ve breast cancer through generation of comprehensive catalogues of somatic mutations in 500 cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

Study EGAS00001000210

Histone acetylome-wide association study on tuberculosis infection

Epigenetic mechanisms are thought to play an important role in the pathogenesis of infectious diseases. Here, we describe the first histone acetylome-wide association study (HAWAS) of an infectious disease, based on genome-wide H3K27 acetylation profiling of peripheral granulocytes and monocytes from subjects with active Mycobacterium tuberculosis (Mtb) infection and healthy controls (135 ChIP-seq datasets).

Study EGAS00001003118

Exome Sequencing in Moebius Syndrome

Möbius syndrome (MBS; MIM 157900) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The etiology of this syndrome has been an enigma since the initial description in 1880 by von Graaefe and in 1888 by Möbius, and it has been debated for decades whether MBS has a genetic or a non-genetic etiology. Here, we reveal various de novo mutations affecting two genes, PLXND1 and REV3L. The finding that de novo mutations can cause Möbius syndrome will have considerable impact on further research, as well as in diagnostics. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA. However, analysis of Plxnd1 and Rev3l-mutant mice revealed that both genetic defects converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation.

Study EGAS00001001250

Clinical Implications of Genomic Alterations in the Tumor and Circulation of Pancreatic Cancer Patients

Pancreatic adenocarcinoma has the worst mortality of any solid cancer. To evaluate the clinical implications of genomic alterations in this tumor type, we performed whole-exome analyses of 24 tumors, targeted genomic analyses of 77 tumors, and used non-invasive approaches to examine tumor-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin regulating genes MLL, MLL2, MLL3, and ARID1A in 20% of patients that were associated with improved survival. We observe alterations in genes with potential clinical utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumor DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, and recurrence by ctDNA is detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

Study EGAS00001001257

HipSci Illumina 450K Methylation 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 Methylation analysis using the Infinium HumanMethylation450 BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with monogenic diabetes.

Study EGAS00001001275

BLUEPRINT DNA methylation profiles of graft donors in allogenic hematopoietic stem cell transplantation

Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. We investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in HLA-matched sibling recipients prior to HSCT. We measured genome-wide DNA methylation levels in peripheral blood of 91 HSCT donors using Illumina Infinium HumanMethylation450 BeadChips. We showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We identified distinct DNA methylation marks in graft donors that are associated with aGVHD severity status in recipients. Together, our findings suggest that ‘epigenetic matching’ of HSCT donor-recipient pairs in a clinical setting may be used in conjunction with genetic matching to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome.

Study EGAS00001001287

Somatic_mutation_and_clonal_evolution_normal_breast_tissue_WGS

Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development.

Study EGAS00001002857

The_Little_Princess_Knowledge_Bank_RNAseq

The purpose of the knowledge bank is to serve as a community resource and to address the following specific questions about Wilms tumour: (1) Do genetic, epigenetic, or transcriptional features predict outcome and thus lend themselves to treatment stratification? (2) What are the genetic drivers of Wilms tumour, considering the entire histological spectrum of Wilms tumour including the most common subtypes classified as intermediate risk?

Study EGAS00001005244

Paroxysmal_neurological_Disorders

We are sequencing the exomes of patients with paroxysmal neurological disorders mainly focusing on migraine and epilepsy. Cases are collected from performance sites of members of the International Headache Genetics consortium and EuroEPINOMICS. Most cases have a strong family history. The study sample will include both cases and controls.

Study EGAS00001000386

Integrated Genomic Analysis of Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a frequent and heterogeneous disease whose genetic alterations determining the clinicobiological behaviour are not fully understood. Here, we describe a comprehensive evaluation of the genomic landscape of 452 CLLs and 54 monoclonal B-lymphocytosis (MBL), a precursor disorder. This study provides an integrated portrait of the genomic landscape of CLL, identifies new recurrent mutations acting as drivers of the disease, and suggests clinical interventions which may improve the management of patients with this neoplasia. The data here included was described in the ICGC-CLL manuscript published by Puente et al (Nature 2015). Note that complementary RNA-seq data generated within the IGCG-CLL can be found in EGAS00001000374.

Study EGAS00001001306

HipSci_RNAseq_Rare_BBS

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 cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Bardet-Biedl syndrome 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 EGAS00001001318

Low_coverage_whole_genome_sequencing_of_samples_from_the__Cretan_Greek_isolate_collection_HELIC_MANOLIS

Whole-genome sequencing at 1x of samples from the Cretan Greek isolate collection HELIC-MANOLIS. Genome-wide association studies of complex traits have been successful in identifying common variant associations, but a substantial heritability gap remains. The field of complex trait genetics is shifting towards the study of low frequency and rare variants, which are hypothesised to have larger effects. The study of these variants can be empowered by focusing on isolated populations, in which rare variants may have increased in frequency and linkage disequilibrium tends to be extended. This work focuses on an isolated population from Crete, Greece. Sequencing is very efficient in isolated populations, because variants found in a few samples will be shared by others in extended haplotype contexts, supporting accurate imputation.

Study EGAS00001000392

Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.

Study EGAS00001002485

JMML targeted sequencing (2013)

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations (Chang, Dvorak et al. 2014). Clinical evolution is heterogeneous, with acute myeloid leukemia (AML) transformation in 1/3 of cases and frequent relapses after hematopoietic-stem-cell transplantation (HSCT), although some patients experience spontaneous remission (Locatelli, Nollke et al. 2005; Matsuda, Shimada et al. 2007; Takagi, Piao et al. 2013; Locatelli and Niemeyer 2015). The initiating lesion incompletely predicts outcome, suggesting the involvement of additional mutations. Genetic profiling of a large JMML cohort (n=118), including whole-exome sequencing (WES) in 30 cases, uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38/case/Mb) and restricted to sporadic (47/78; 60%) or NF1-associated (8/8; 100%) JMML. Multiple concomitant genetic hits were identified targeting the RAS pathway in 13/78 (17%), RAC2D63V, which activates the PI3K/PDK1/AKT and the mTORC2 pathways, and a novel pathway for JMML, the polycomb repressive complex 2 (PRC2), in 26/78 (33%) of the sporadic JMML cases. Interestingly, PRC2 imbalance was recently shown to synergize with RAS activation (De Raedt, Beert et al. 2014). JMML outcome was associated to the mutational profile, suggesting a dose-dependent effect for RAS-pathway activation, distinguishing very aggressive JMML rapidly progressing to AML.

Study EGAS00001001324

Genomic profiling of esthesioneuroblastoma

We performed whole exome and whole genome sequencing on a cohort of esthesioneurblastoma to understand the genetic underpinnings of this neoplasm.

Study EGAS00001003225

IBD_Whole_Genome_Sequencing

We will sequence at 15X coverage the genomes of 1536 IBD patients. These samples are currently onsite at Sanger and made available for sequencing via our collaboration with the UK IBD Genetics consortium. 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 EGAS00001002238

BLUEPRINT Bisulfite-seq (CNAG)

Bisulfite-Seq

Study EGAS00001000418

Prostate_Cancer_Whole_Genome_Validations

We propose to definitively characterise the somatic genetics of Prostate cancer through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing. This study will aim to validate the findings of the whole genome study by re-sequencing regions of interest using a bespoke pulldown bait. See ICGC website for more information: http://icgc.org/icgc/cgp/70/508/71331

Study EGAS00001000427

Genomes of Relapsing Neuroblastoma

Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs, but the molecular mechanisms behind this process are poorly defined. We here used whole-exome sequencing, mRNA expression, array CGH and DNA methylation analysis to holistically characterize 16 paired samples from neuroblastoma patients at diagnosis and relapse. The mutational burden significantly increased in relapsing tumors accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and patient-specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target gene, YAP. Recurrent new mutations in HRAS, KRAS, DOCK8 and genes mediating cell-cell interaction in 13/16 relapse tumors also indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed first light on genetic alteration frequency, identity and evolution in neuroblastoma.

Study EGAS00001001387

DERMATLAS__Hidradenoma_papilliferum_WES

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 hidradenoma papilliferums.

Study EGAS00001005714

The Southern African Human Genome Programme

The Southern African Human Genome Programme (SAHGP) is a national and regional initiative that aims to unlock the unique genetic character of southern African populations. Its vision is to improve quality of life through understanding human genetic diversity. It is timely to advance the SAHGP initiative since global genomic initiatives are increasingly pointing to populations in Africa, more specifically the San and Khoe from southern Africa, as harbouring the most ancient genetic signatures among the living populations of the world. Studies on African populations have already generated a wealth of information upon which the SAHGP can build. This information will be used to promote and support genomic research programmes both nationally and regionally to address critical questions that would benefit the people of our region. The SAHGP aims to make a significant contribution to the understanding of DNA variation among southern Africans and how this impacts on the health of the people of this region. Aims of the SAHGP: To develop capacity for genomic research in southern Africa; To establish sustainable resources for genomic research in the region; and To translate knowledge and information into improvements in human health in the region. The objective is to derive the maximum benefit from the SAHGP, and that the data should be widely shared with the scientific community for the benefit of the people of the sub-continent and beyond.

Study EGAS00001002639

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

B-cell prolymphocytic leukemia (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 EGAS00001003274

Harnessing_transposons_for_drug_resistance_gene_discovery_in_cancer

This study involves a forward genetic screen to identify common insertion sites in drug resistant clones. We will be utilising piggybac transposon systems in order to generate multiple drug resistant clones in a range of human cancer cell lines.

Study EGAS00001000468

Egypt_Genome_Project___high_coverage_whole_genome_sequencing

All humans outside Africa are descendants of the same single exit, usually dated at 50-70 thousand years ago. However, the route taken out of Africa is still debated. The two main candidates are a northern route via Egypt and the Levant, or a southern route via Ethiopia and the Arabian Peninsula. We are generating genetic data to evaluate these two possibilities. In this study we propose to generate high-coverage sequencing data for 3 Egyptian samples.

Study EGAS00001000482

Transcriptional_profiling_of_tauopathies_in_human_IPS_derived_neurons

This project is a pilot study, in collaboration with Maria Grazia Spillantini and Mariangela Iovino (Cambridge Centre for Brain Repair), to investigate the utility of IPS-derived neurons for the study of neurodegenerative disorders. Our aim is to characterise the transcriptional consequences of tauopathies using neurons derived from differentiated IPSCs as a model system. We will use IPS cells derived from six individuals, four with known mutations in the tau protein, 2 without. RNA will be extracted at Day 0 and Day 65 of differentiation by which time the neuronal tauopathy is apparent. RNA will be extracted and the transcriptome of each line characterised using RNAseq. We will then search for genes that are differentially expressed between the transcriptomes of individuals with tau mutations versus those in controls. My lab will analyse the RNAseq data, comparing both affected and controls and both time-points, to establish candidate genes. Darren Logan’s lab, along with our collaborators, will experimentally verify and further investigate these genes in additional lines and animal models. From this analysis we will generate a list of candidate genes that are differentially expressed between cases and controls. This study will not only help us understand the molecular basis of tauopathies, but also identify gene candidates for biomarkers of neurodegenerative disease. It will serve as a proof of principle for future planned studies into generating and transcriptomically analysing an allelic series of Tau mutations in IPSCs with a controlled genetic background.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 EGAS00001000382

Assessment_of_genetic_and_epigenetic_variation_in_human_IPS_cells

In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs but it is unlcear whether some cell types carry through fewer mutations through reprogramming (either due to mutations present in the primary cells, or mutations accumulated during reprogramming). Through in depth analysis of hiPSCs generated from different somatic cells, it will be possible to assess the variation in genetic stability of different cell types.

Study EGAS00001000492

MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

Age and stage of disease at diagnosis is associated with outcome in neuroblastoma. A previous study identified ATRX point mutations and in-frame deletions in older patients with stage 4 disease. To validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables, we collaborated with the Children’s Oncology Group and sequenced the entire ATRX genomic locus in 475 neuroblastoma tumor samples to validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables. Older age at diagnosis, stage 4 disease, and unfavorable histology were significantly associated with mutations in the ATRX gene; MYCN amplification was mutually exclusive from ATRX mutations. To directly test if ATRX mutations and MYCN amplification are incompatible in neuroblastoma, we mutated the ATRX gene in MYCN amplified neuroblastoma cell lines and ectopically expressed MYCN in ATRX mutant neuroblastoma cell lines. Both approaches showed that ATRX and MYCN amplification are incompatible in neuroblastoma in culture and in vivo. To gain a better understanding of the underlying molecular and cellular mechanisms of this incompatibility, we performed a series of experiments including telomere analysis, epigenetic profiling, electron microscopic analysis and metabolic profiling. We discovered that induction of MYCN expression in ATRX mutant neuroblastomas cells leads to metabolic reprogramming, mitochondrial dysfunction, increased reactive oxygen species and replicative stress. We propose that this leads to synthetic lethality in ATRX mutant neuroblastomas because of the underlying replicative stress in those cells as a result of dysfunction of this essential histone chaperone.

Study EGAS00001003257

High_powered_complex_trait_association_mapping_through_whole_genome_sequencing_of_a_selected_subpopulation_of_the_INGI_Val_Borbera_genetic_isolate

The VBSEQ project aims to combine available extensive genetic and phenotypic data to the latest high-throughput genome sequencing technology and ad hoc statistical analysis to identify new rare genetic variants underlying complex traits. Up to 100 Val Borbera samples will be sequenced to a 6x depth.

Study EGAS00001000398

Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathie

Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium,including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), andarrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity andmortality. These diseases are genetically diverse and associated with rare mutations ina large number of genes, many of which overlap among the phenotypes. To betterinvestigate the genetic overlap between these three phenotypes and to identify newgenotype-phenotype correlations, we designed a custom gene panel consisting of 115genes known to be associated with cardiomyopathic phenotypes and channelopathies.A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC,was recruited for the study on the basis of more severe phenotypes and family historyof cardiomyopathy and/or sudden death.

Study EGAS00001002506

Genetic and epigenetic characterization of adenoid cystic carcinoma

Translocation events are frequent in cancer and may create chimeric fusions or regulatory rearrangements that drive oncogene overexpression. Although regulatory rearrangements are increasingly recognized in hematopoietic and even solid tumors, the underlying mechanisms remain obscure. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a unifying theme in adenoid cystic carcinoma (ACC). Whole genome sequencing data and chromatin state maps for 13 primary tumors and xenografts reveal distinct chromosomal rearrangements that juxtapose super-enhancer clusters to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers physically interact with the MYB promoter. Remarkably, the MYB product itself binds to the translocated enhancers, thus creating a positive feedback loop that sustains its own expression. MYB also binds a large number of active enhancers that drive opposing regulatory programs in alternate cell lineages in ACC. MYB cooperates with the transcription factor TP63 in the myoepithelial component of the tumors, but promotes a Notch program in the luminal epithelial component. Bromodomain inhibitors, which disrupt enhancer function, slow tumor growth in ACC primagraft models in vivo, but are ineffective against high grade tumors that harbor activating mutations in the Notch pathway. Thus, our study identifies super-enhancer translocations as a unifying feature of ACC, and provides insight into the mechanism by which sustained MYB overexpression drives alternate cell fates in this disease.Processed ChIP-seq data is available on GEO under accession number GSE76465.

Study EGAS00001001457

WGS_of_healhy_mesothelial_cells_and_primary_mesothelima_cell_lines

Mesothelioma is a rare and aggressive cancer associated with previous exposure to asbestos. Currently there are no effective treatments for mesothelioma and majority of patients will die within a year after diagnosis. Although a large number of preclinical and clinical trials assessed the efficacy of various therapuetic modes, none of the tested molecules entered the clinic. Thus, to better understand what drives mesothelioma carcinogenesis and to identify novel targets for therapy, here we aim at performing WGS of heathy mesothelial cells and a panel of mesothelioma cells lines. Primary mesothelial cell lines were established in prof. Marciniak lab from human pleural specimens, while primary mesothelioma cell lines were obtained from MesobanK. Both models constitute low passage cell lines and therefore should closely represent genetics of the original tissue.

Study EGAS00001005559

The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

Study EGAS00001002153

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