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• Poly(A) RNA sequencing of hepatocellular carcinoma tumors and their matched noncancerous liver tissues

  Background & Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002337

• Recurrent epimutations activate gene body promoters in primary glioblastoma

  Aberrant DNA hypomethylation may play an important role in the growth rate of glioblastoma (GBM), but the functional impact on transcription remains poorly understood. We assayed the GBM methylome with MeDIP-seq and MRE-seq, adjusting for copy number differences, in a small set of non-glioma CpG island methylator phenotype (non-G-CIMP) primary tumors. Recurrent hypomethylated loci were enriched within a region of chromosome 5p15 that is specified as a cancer amplicon and also encompasses TERT, encoding telomerase reverse transcriptase, which plays a critical role in tumorigenesis. Overall, 76 gene body promoters were recurrently hypomethylated, including TERT and the oncogenes GLI3 and TP73. Recurring hypomethylation also affected previously unannotated alternative promoters, and luciferase reporter assays for three of four of these promoters confirmed strong promoter activity in GBM cells. Histone H3 lysine 4 trimethylation (H3K4me3) ChIP-seq on tissue from the GBMs uncovered peaks that coincide precisely with tumor-specific decrease of DNA methylation at 200 loci, 133 of which are in gene bodies. Detailed investigation of TP73 and TERT gene body hypomethylation demonstrated increased expression of corresponding alternate transcripts, which in TP73 encodes a truncated p73 protein with oncogenic function and in TERT encodes a putative reverse transcriptase-null protein. Our findings suggest that recurring gene body promoter hypomethylation events, along with histone H3K4 trimethylation, alter the transcriptional landscape of GBM through the activation of a limited number of normally silenced promoters within gene bodies, in at least one case leading to expression of an oncogenic protein.

  Study EGAS00001000685

• DNA methylation and the adverse metabolic outcomes of adiposity

  Overweight and obesity affect ~1.5 billion people worldwide, and are major risk factors for type-2 diabetes (T2D), cardiovascular disease and related metabolic and inflammatory disturbances.1,2 Although the mechanisms linking adiposity to its clinical sequelae are poorly understood, recent studies suggest that adiposity may influence DNA methylation,3-6 a key regulator of gene expression and molecular phenotype.7 Here we use epigenome-wide association to show that body mass index (BMI, a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci at P<1x10-7, range P=9.2x10-8 to 6.0x10-46; N=10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find the methylation loci are enriched for functional genomic features in multiple tissues (P<0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P<9.0x10-6, range P=5.5x10-6 to 6.1x10-35, N=1,785 samples). The methylation loci identified highlight genes involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future type-2 diabetes (relative risk per 1SD increase in Methylation Risk Score: 2.3 [2.07-2.56]; P=1.1x10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type-2 diabetes and other adverse clinical consequences of obesity.

  Study EGAS00001001922

• UK10K NEURO FSZNK

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This Finnish schizophrenia sample set has been collected from a population cohort using national registers. The entire sample collection consists of 2756 individuals from 458 families of whom 931 are diagnosed with schizophrenia spectrum disorder. Families outside Kuusamo (n=288) all had at least two affected siblings. All diagnoses are based on DSM-IV and for a large fraction of cases there is cognitive data.For further details/descriptions with regard to this data set please contact Tiina Paunio (tiina.paunio@thl.fi)

  Study EGAS00001000119

• 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

• Study on the consequences of prenatal famine exposure on DNA methylation.

  The potential of the epigenome to undergo environmentally-induced changes during early development is central to its postulated role in human disease. Here, we report a genome-scale view of DNA methylation differences after early gestational malnutrition that was caused by the Dutch Hunger Winter, a severe famine at the end of World War II. We adopted an annotation guided analysis of reduced-representation bisulfite sequencing data generated in 24 middle-aged individuals who had been exposed to famine in utero and 24 unexposed sibling controls. We observed differential DNA methylation primarily at genomic regions with regulatory potential, including enhancers active during early development. In-depth annotation of 181 prenatally-induced differentially methylated regions (P-DMRs) showed that they were predominantly located in gene bodies and co-occurred with histone marks denoting an active state. In line with the early gestational timing of the exposure, the P-DMRs mapped to genes that were enriched for differential expression patterns during blastocyst development and early organogenesis. Validation and further explorative analyses of 6 P-DMRs mapping to SMAD7, CDH23, INSR, RFTN1, CPT1A and KLF13 highlighted the critical role of gestational timing, indicated that differential methylation extended along pathways involved in growth, development and metabolism, and suggested associations with birth weight and serum LDL cholesterol in adulthood and confirmed an enhancer function for the INSR and CPT1A P-DMRs. Our results point toward a link between prenatal malnutrition and epigenetic modulation of growth and lipid metabolism that may underlie the adverse metabolic phenotype of exposed individuals in later life.

  Study EGAS00001000668

• Quantification of chromosomal copy number aberrations by shallow whole-genome sequencing

  Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures.Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice very useful profiles can be obtained with 0.1 fold genome coverage. We improve on previous methods by; first, implementing a combined correction for sequence mappability and GC content, and second, applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions were previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1,000 samples, most of which were obtained from the fixed tissue archives of over 25 institutions.We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches, and better copy number data than high-resolution microarrays at substantially lower cost.

  Study EGAS00001000642

• Prediction and quantification of splice events from RNA-seq data

  Analysis of splice variants from short read RNA-seq data remains a challenging problem. Here we present a novel method for the genome-guided prediction and quantification of splice events from RNA-seq data, which enables the analysis of unannotated and complex splice events. Splice junctions and exons are predicted from reads mapped to a reference genome and are assembled into a genome-wide splice graph. Splice events are identified recursively from the graph and are quantified locally based on reads extending across the start or end of each splice variant. We assess prediction accuracy based on simulated and real RNA-seq data, and illustrate how different read aligners (GSNAP, HISAT2, STAR, TopHat2) affect prediction results. We validate our approach for quantification based on simulated data, and compare local estimates of relative splice variant usage with those from other methods (MISO, Cufflinks) based on simulated and real RNA-seq data. In a proof-of-concept study of splice variants in 16 normal human tissues (Illumina Body Map 2.0) we identify 249 internal exons that belong to known genes but are not related to annotated exons. Using independent RNA samples from 14 matched normal human tissues, we validate 9/9 of these exons by RT-PCR and 216/249 by paired-end RNA-seq (2 x 250 bp). These results indicate that de novo prediction of splice variants remains beneficial even in well-studied systems. An implementation of our method is freely available as an R/Bioconductor package SGSeq.

  Study EGAS00001001026

• Associations between APOE status and cognitive ability across the lifecourse

  The association between APOE genotype and cognitive function suggests a positive role for the e2 allele and a negative role for the e4 allele. Both alleles have relatively low frequencies in the general population, hence meta-analyses have been based on many small, heterogeneous studies. Here we report the APOE-cognition associations in the largest single analysis to date. APOE status and cognitive ability were measured in 18,337 participants from the Generation Scotland study between 2006 and 2011. The age range was 18-94 years with a mean of 47 (SD 15). Four cognitive domains were assessed: verbal declarative memory (paragraph recall), processing speed (digit symbol substitution), verbal fluency (phonemic verbal fluency), and vocabulary (Mill Hill synonyms). Linear regression was used to assess the associations between APOE genetic status and cognition. Possession of the e4 allele was associated with lower scores on the measures of memory and processing speed in subjects aged >60. Across all age ranges, the e4 allele was linked to better verbal fluency scores. In younger subjects (≤60 years) the e4 allele was linked to higher vocabulary scores. There were no associations between the e2 allele and cognitive ability. As seen in previous meta-analyses, the APOE e4 allele is linked to poorer cognitive performance in the domains of memory and processing speed. By contrast, positive associations were seen between the e4 allele and measures of verbal fluency and vocabulary. All associations were relatively small and, in many cases, nominally significant despite the very large sample size.

  Study EGAS00001001235

• Transcriptome_human_nasal_epithelium

  1. Odors are detected, firstly, by olfactory sensory neurons (OSNs) in the olfactory epithelium of the nose. This neurons then project directly to the olfactory bulb in the brain. Olfaction depends on cellular regeneration of the OE, olfactory bulb and hippocampus, and on their continual re-wiring. The olfactory neural pathway includes regions of the frontal, temporal and limbic brain, which in turn overlap with brain areas involved in brain disorders. OSNs are the only aspect of the human brain exposed to the external environment. This not only makes them vulnerable to environmental changes, but also accessible for biomedical studies.We have already sequenced and developed a protocol for analyzing the transcriptome of mouse main olfactory epithelium and single OSNs. We propose here to perform a similar study for samples from the human olfactory epithelium. We have developed a minimally invasive method for obtaining human OSNs, among other cells from the nasal epithelium. In this experiment, we have obtained cell samples from the olfactory epithelium, including OSN, from healthy volunteers. We would like to further characterize them by RNA sequencing. This will give us valuable insight into human olfaction. It will also provide a first step into a new avenue to study, and find biomarkers for, brain diseases though the analysis of these easily available neurons. 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 EGAS00001001294