3845 results for "*geneti*"

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• PSCP_bisulphite_analysis_in_hESCs

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. 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 EGAS00001001625

• Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

  Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3' untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.SIGNIFICANCE: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes.

  Study EGAS00001001653

• 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

• Integrative_genome_profiling_in_AML

  AML emerges as a consequence of accumulating independent genetic aberrations that direct regulation and/or dysfunction of genes resulting in aberrant activation of signalling pathways, resistance to apoptosis and uncontrolled proliferation. Given the significant heterogeneity of AML genomes, AML patients demonstrate a highly variable response rate and poor median survival in response to current chemotherapy regimens. For the past 4 years we have conducted gene expression profiling on purified bone marrow populations equating to normal haematopoietic stem and progenitor cells from healthy subjects and patients with de novo AML in order to identify AML signatures of aberrantly expressed genes in cancer versus normal. We are now applying a series of bioinformatic methodologies combined with clinical and conventional diagnostic data to establish novel genomics strategies for improved prognostication of AML. Additionally, we use our AML signatures to unravel oncogenic signalling pathway activities in AML patients and test inhibitory drugs for these pathways inn preclinical therapeutic programmes. We consider that superimposing GEP and clinical data for our AML patient cohort with additional data on their mutational status will significantly improve the prognostic power of the study as well as unravel yet unknown mutations associated with aberrant signalling activities of oncogenic pathways.

  Study EGAS00001000858

• HipSci HumanExome BeadChip analysis-Healthy volunteers

  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 from healthy volunteers.

  Study EGAS00001000866

• Guardians_of_the_genome__protecting_DNA_from_endogenous_sources_of_damage_

  Analysis of mutational signatures caused by DNA repair defects in human induced pluripotent stem (iPS) cells. A reference human iPS cell line will be used for genetic manipulation to introduce homozygous knockouts of 100 genes known to be involved in or connected to DNA repair or DNA editing. Following a defined period of growth after homozygous knockout of each gene, sub clones will be generated and sequenced. The progenitor “parental” IPS cell line will be used to generate reference sequence data, in order to determine the mutational signature acquired due to the gene knockout. This is a pilot study to investigate the effects of oxygen conditions and growth period on mutations acquired

  Study EGAS00001000874

• Study on the proliferation history of colorectal adenomas

  Mismatch repair (MMR) deficient colorectal adenomas are composed of transformed cells that descend from a common founder and progressively accumulate genomic alterations but their proliferation history is still largely unknown. Here we rebuilt the proliferation history of four MMR deficient colorectal adenomas from male individuals by deep sequencing the X chromosome and mapping the somatic mutations that were progressively acquired during tumor growth. We developed a novel method to call high and low frequency mutations, to cluster them according to their frequencies and rebuild the proliferation trees directly from these mutation clusters using a recursive algorithm. The trees of all four lesions were formed of a dominant subclone that coexisted with other genetically heterogeneous subpopulations of cells. Despite this similar hierarchical organization, however, the growth dynamics varied among and within tumors, likely depending on a combination of tumor-specific genetic and environmental factors. Our study provides insights into the biological properties of individual MMR deficient colorectal adenomas that may influence their growth and also the response to therapy. Extended to other solid tumors, our approach could inform on the mechanisms of cancer progression, thus providing insight into the best choice of cancer treatment methods.

  Study EGAS00001000883

• 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 EGAS00001000048

• WTCCC3_Anorexia_Nervosa

  As part of the Genetic Consortium for Anorexia Nervosa (GCAN) and Wellcome Trust CaseControl Consortium 3 (WTCCC3), we have amassed the largest anorexia nervosa (AN)sample in the world (~4,000). Following the WTCCC3 GWAS, we secured funding from theKlarman Family Foundation to extend the genetic analyses to variants on the exome chip(CoreExome array). This pre-lim relates to carrying out genotyping on the CoreExome arrayon up to a maximum of 580 new samples.

  Study EGAS00001000913

• Developmental_Dysplasia_of_the_Hip__DDH_

  The National Joint Registry for England and Wales (NJR) has become established as one of the largest repositories of clinical information about patients undergoing hip and knee replacement. The primary aim of this proposal is to examine the feasibility of adding value to that clinical information by partnering it with a DNA dataset to allow its use to be extended to the study of the underlying pathogenesis of diseases of the hip and knee, and the complications of their treatment. We will do this 1) by establishing a mechanism for accessing and linking pseudo-anonymised demographic and phenotype data between the NJR database and the proposed DNA Biobank; 2) by validating the collection of postal DNA samples from consenting NJR patients; and 3) by genotyping genome-wide 900 patients with the condition developmental dysplasia of the hip (DDH) to find variants that play a role in this heritable condition. The successful demonstration that the NJR can be used to establish a DNA Biobank will provide a powerful platform to examine the genetic basis for a wide range of joint diseases, and the complications of their treatment. This proposal is to carry out the genotyping portion of this project on the current CoreExome array

  Study EGAS00001000916

• Genome_wide_association_study_of_vaccine_responses_in_infants_living_in_the_Developing_World__VaccGene___Phase_II_African_Cohorts

  Human genetic heterogeneity accounts for approximately 70% of the observed variability inresponse to common childhood vaccinations. Identifying the elements of this heterogeneitywill enable the development of vaccines which have improved clinical and cost effectivenessthrough rational adjuventation approaches, or by targeting particular at-risk or responsivesubgroups. The studies published to date have been limited in terms of the number of vaccinesubtypes analysed, diversity of the populations included, sample sizes and breadth of otherenvironmental and lifestyle variables which may explain some of the remainder of variation inthe response to each vaccine. Nevertheless, these studies have proposed that the geneswhich harbour the variants associated with vaccine responsiveness reside within regions ofthe genome associated with immune function such as the HLA locus and FOXP1and ITGAL.We are proposing one of the largest genome-wide association studies of vaccine responseever undertaken, which will provide unparalleled power to identify the genetic factorsassociated with the response to all of the most commonly used childhood vaccinesworldwide. For the first phase of the project (Prelim I0308) we genotyped ca. 1,400 childrenfrom the Entebbe Mother and Baby (EMaB) study, an ongoing birth cohort in southernUganda, using the Illumina HumanOmni2.5-8 chip. Analyses for response to vaccinationagainst diphtheria, tetanus, pertussis, Haemophilus influenzae, measles, hepatitis B and BCGare now underway. Working alongside other ongoing studies, we plan for the second phaseof the project to expand sample sizes to up to 7,000 individuals in total. This large cohort willinclude 1,500 South African infants, 500 Burkina Faso infants, 1,800 children from Ecuadorand up to 1,800 from a variety of countries (MAL-ED Consortium). The principal measuredphenotypes will be the serological responses at 6 or 12 months of age to the vaccinesadministered to all enrolled children as part of expanded programme of immunisation in allcountries. As for the primary Ugandan study the responses will be analysed as quantitativetraits using mixed model (GEMMA) analyses following imputation using a combined 1000Genome and African Genome Variation Project reference panel. The data will be analysed asone large discovery mega-analysis to maximise the power of finding the relevant associatedvariants. Interim GWAS analyses will be performed on each population to test for populationspecific signals. Other phenotypes that will be assessed in the new studies includequantitative response to BCG, rotavirus and pneumococcal vaccines (South Africa, Ecuadorand Uganda), clinical and immunological response to malaria vaccines (Burkina),immunological correlates of atopy (Ecuador and Uganda) and malaria infection (Burkina,Ecuador and Uganda) in addition to non-communicable disease traits such as blood pressurepage 1[A8] If applicable, provide text (abstract) which will accompany data for this study in the ENA/EGA.[A9] Does this project use samples?[A10] Please choose which types of sample you will be using[A12] Please state the anticipated date (month/year) samples will be available in-house (if known). If samples arealready in-house, type 'in-house' here. Please note that for sequencing, genotyping and microarrays this is essentialfor scheduling the work.[A13] Please state the anticipated project start date (month/year).[A14] Please state the project duration (months).[A15] Please read WTSI's Data Sharing Policy and Guidelines, then explain your data sharing plans for the project[A16] Are the data sharing plans of this project compliant with the Institute's Guidelines?[A17] Are there any conflicts of interest related to this proposal?(Uganda).We are requesting funds to genotype on the Illumina HumanOmni2.5-8 platform 2,000 Africaninfants recruited through ongoing maternal and child vaccine clinical trials (againstpneumococcus in Soweto, South Africa, and malaria in Banfora, Burkina Faso). The DNAfrom the Burkina cohort is at the University of Oxford and ready to be shipped, while the DNAfrom the South African cohort will be available by mid-2014. Appropriate consent for geneticanalyses has been acquired for the proposed study cohorts from both local ethics committeesand UK-based Committees.

  Study EGAS00001000918

• Therapeutic Resistance to PI3K-alpha Inhibitors

  We have studied the tumor genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response on BYL719, but eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic lesions were collected for further analysis. In order to identify possible genetic determinants of acquired resistance to PI3Kα inhibition, we took a three-step approach. First, we examined both the primary tumor (before BYL719 treatment) and the new lung metastasis by whole genome sequencing (DNA from the spleen was used as a normal control). Then, we analyzed the primary tumor, lung metastasis, and the peri-aortic lesion that remained stable (responding) at the time of progression to BYL719 therapy by whole exome sequencing. Finally, to confirm and expand our findings, we sequenced the primary tumor and all the metastatic lesions to >500-fold coverage using a custom targeted deep-sequencing assay, MSK-IMPACT. Using this 3-step approach, we have demonstrated that patient’s lesion underwent parallel genetic evolution at multiple metastatic sites with different PTEN genomic alterations leading to a convergent PTEN- null phenotype resistant to PI3Kα inhibition. In order to expand our observations, we analyzed paired samples (pre-treatment and at progression) from six additional patients enrolled in the BYL719 trial. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumor were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3K-p110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI3Kα inhibition.

  Study EGAS00001000991

• Ischemic stroke in a Swedish case-control study.

  Background. Genetic risk scores (GRS), summing up the total effect of several single nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS, based on 29 SNPs discovered by genome-wide association studies (GWAS) and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other “traditional risk factors”, also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Methods and results. Twenty-nine SNPs were genotyped in 3,677 stroke cases and 2,415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the entire material, and separately for the three samples. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the entire material [OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS p=0.003] with similar trends in all three samples; LSR [1.050 (0.967-1.140)]; p=0.25], MDC [1.168 (1.060-1.288); p=0.002] and SAHLSIS [1.124 (0.997-1.267); P=0.055]. Measures of discrimination and reclassification improved marginally using the GRS. Conclusions. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension.

  Study EGAS00001000936

• Genome-wide prediction of human embryos

  BACKGROUND: Preimplantation genetic diagnosis (PGD) enables profiling of embryos for genetic disorders prior to implantation. The majority of PGD testing is restricted in the scope of variants assayed or by the availability of extended family members. While recent advances in single cell sequencing show promise, they remain limited by bias in DNA amplification and the rapid turnaround time (<36 h) required for fresh embryo transfer. Here, we describe and validate a method for inferring the inherited whole genome sequence of an embryo for preimplantation genetic diagnosis (PGD). METHODS: We combine haplotype-resolved, parental genome sequencing with rapid embryo genotyping to predict the whole genome sequence of a day-5 human embryo in a couple at risk of transmitting alpha-thalassemia. RESULTS: Inheritance was predicted at approximately 3 million paternally and/or maternally heterozygous sites with greater than 99% accuracy. Furthermore, we successfully phase and predict the transmission of an HBA1/HBA2 deletion from each parent. CONCLUSIONS: Our results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos.

  Study EGAS00001001020

• Genetic_profiling_of_mucosal_melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence ‘normal’ DNA from the same individual, where possible, to exclude germline variations.

  Study EGAS00001001115

• DKFZ-HIPO Project H021/NCT MASTER

  Clinical genome and transcriptome sequencing in younger adults with advanced-stage cancer across all histologies: DKFZ-HIPO Project H021 (http://www.hipo-heidelberg.org/hipo2/index.php/menu-item-2/32-021-prospective-genetic-characterization-of-tumors-from-individual-patients-of-special-interest) / NCT MASTER (http://www.nct-heidelberg.de/forschung/nct-master.html)

  Study EGAS00001000948

• Clinical and Molecular Investigation of Familial CEBPA-mutated Acute Myeloid Leukaemia

  Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are clonal diseases arising from the sequential acquisition of genetic aberrations in haematopoietic stem cells. Whilst the aetiology is predominantly sporadic, rare reports describe the autosomal dominant inheritance of MDS and AML (familial MDS/AML), often presenting in younger patients (<40 years of age) with a germline mutation in one of three haematopoietic transcription factors: RUNX1, CEBPA and GATA2. The clinical recognition of familial disease can be challenging due to wide variations in phenotype, latency and transmission, complicated further by the patients’ awareness and reporting of affected relatives. Distinct clinical manifestations have however been reported for each genetic subtype and whilst RUNX1 and GATA2 mutations can harbour prolonged dysplastic or cytopenic phases, germline CEBPA mutations universally present with AML de novo. Our group were the first to describe germline CEBPA mutations in 3 related individuals, all of whom developed AML between 10-30 years of age. The initial pedigree together with those described in the intervening period, were predominantly isolated case reports with limited follow up, hence long term outcomes for this group of patients remain poorly defined. This contrasts with CEBPA mutations occurring in 10-15% of sporadic AML with normal karytoype (NK-AML), where double mutations (CEBPAdm, found in approximately 50% of all CEBPA-AML) are considered a unique molecular entity, associated with favourable clinical outcomes. In sporadic and familial CEBPAdm AML, N’ terminal mutations enforce translation of the shorter P30-kDa isoform and are typically accompanied by C’ terminal insertions or deletions (disrupting the DNA-binding and/or Leucine zipper domains). Definition of the full molecular landscape awaits extensive whole exome sequencing, although GATA2 mutations (targeting the Zinc Finger 1, ZF1, domain) have been reported in 20-40% of sporadic CEBPAdm AML and recent targeted resequencing analysis revealed a further association with WT1 mutations. With minimal clinical and molecular information available for familial CEBPA-AML, we are often consulted regarding the management of this unique patient population. To address this need, we have investigated a multi-centre cohort of families with germline CEBPA mutations, providing extended clinical follow up, whole exome profiling of secondary mutations and molecular analysis of relapsed disease.

  Study EGAS00001000949

• Genome-wide SNP genotyping and DNA methylation epigenotyping of African rainforest hunter-gatherers and neighbouring agriculturalists

  The epigenomic landscape of the human genome, in particular DNA methylation, is increasingly recognised as an important driver of phenotypic diversity in health and disease. However, the impact that genetic variation and changes in lifestyle and ecological habitat have on this epigenetic mark remains unknown. To address this question, we analysed genome-wide SNP and DNA methylation profiles of 362 individuals from African populations of rainforest hunter-gatherers and sedentary farmers with different past and present lifestyles and ecologies.

  Study EGAS00001001066

• Functional_characterisation_of_CpG_islands_in_human_and_mouse_tissues

  Tissue-specific methylation patterns suggest a role for CpG island (CGI) methylation in differentiation and cell-type-specific gene regulation. We have applied CXXC affinity purification (CAP), MBD affinity purification (MAP) and chromatin immunoprecipitation (ChIP) in combination with solexa sequencing to investigate the extent and functional significance of CGI methylation in sperm, blood, cerebellum and ES cells for both human and mouse.

  Study EGAS00001000075

• TGS___Comprehensive_Molecular_Characterization_of_Colorectal_Cancer_Metastases__MOSAIC_

  Systematic next generation sequencing efforts are beginning to define the genomic landscape across a range of primary tumours, but we know very little of the mutational evolution that contributes to disease progression.We therefore propose to obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in a cohort of matched primary and metastatic colorectal cancers, and additionally to explore the extent to which those mutations identified as recurrent in the metastatic setting are able to subvert normal biological processes using both genetically engineered mouse models and established cancer cell lines. This study will enable us to define to what extent primary tumour profiling can capture the biological processes operative in matched metastases as well as the significance of intratumoural heterogeneity.

  Study EGAS00001000958

• CRLF2_sequencing_project_Exomes

  I hope to gain insight into novel genetic aberrations present in these patients that will highlight important pathways that are involved in this subtype of leukaemia. It would be interesting to see if the mutations and pathways that are activated are consistent between the patients, or differences are observed dependent upon whether the patient has the translocation or the PAR1 deletion. Of note is the high association with either numerical gains of chromosome X or numerical/structural abnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. I hope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. By including the three patients that are normal for CRLF2, but have consistent genetic abnormalities found in the experimental cohort, I expect to find genetic differences between these two groups that will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000081

• Bone_Cancer___Rare_Types_Whole_Genome

  We propose to definitively characterise the somatic genetics of a selection of rare bone cancers through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing.

  Study EGAS00001000501

• Fetal hemoglobin in sickle cell disease patients from Tanzania

  Levels of fetal hemoglobin have been associated with differences in severity and outcome of sickle cell disease (SCD). While some genetic associations have been reported between SNPs and HbF level, little of the variance in the trait is explained, and most studies have focused on African American, rather than African samples. We have carried out a GWAS in a collection of SCD patients from Dar es Salaam, Tanzania. This sample represents a diverse, metropolitan collection of individuals from East Africa. Omni 2.5M genotypes and HbF levels (measured after 5 years of age) are available.

  Study EGAS00001000990

• McGill Epigenomics Mapping Centre

  The McGill Epigenomics Mapping Centre (EMC) and Data Coordination Centre (EDCC) were established in 2012 at the McGill University and Genome Quebec Innovation Centre (Montreal, Canada) to support large-scale human epigenome mapping for a broad spectrum of cell types and diseases. Previous epigenetic studies have provided profiles of specific chromatin marks in relation to basic biological processes, and future studies of molecular mechanisms must build upon these proofs-of-concept by integrating sequence-based variation with multiple levels of epigenetic and transcriptional regulation across the genome of human tissues and animal disease models. This project leverages the high-throughput sequencing infrastructure and expertise in genomics and transcriptomics at the McGill Innovation Centre to carry out this research. Controlled access to the data by collaborators and the greater scientific community is gained via a portal, which takes advantage of Compute Canada high-performance computing cluster resources to manage the large volume of data associated from the generation of reference epigenome maps. McGill University is one of two Canadian mapping and data coordination centres, the other based at the Michael Smith Genome Sciences Centre in Vancouver, British Columbia. The generation of comprehensive epigenome maps at McGill University is part of a larger international effort that is coordinated by the International Human Epigenome Consortium (IHEC), whose overall long-term objective is to determine the extent to which the epigenome shapes human populations over generations and in response to the environment. This project is funded under the Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) by the Canadian Institutes of Health Research and by Genome Quebec, with additional support from Genome Canada. The computing and networking infrastructure, and part of the software development, are provided by Compute Canada and CANARIE.

  Study EGAS00001000995

• Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

  Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, aflatoxin B1 and HBV infection. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV) and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF/CCND1 amplification, TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 24% of the tumors, we identified genetic alterations potentially targetable by FDA-approved drugs. In conclusion, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.

  Study EGAS00001001002