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• Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

  Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. an in-house developed tool (QURNAS) was used to calculate the enrichment score (ERS) for each splicing event. RNA enrichment of NF1 and SPRED1 was done using SPET (NUGEN - NF1 only) and using SureSelect (Agilent - NF1 and SPRED1).

  Dataset EGAD00001007978

• Tumor-derived cell lines as pharmacogenomic models to predict therapeutic vulnerabilities in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. Here, we performed multi-omic analysis including whole-exome, RNA and microRNA sequencing in a series 34 LCCL. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular “proliferation class” of HCC.

  Dataset EGAD00001004938

• DNA repair in BLM deficient hiPSCs

  We are aiming to investigate repair of a double strand break (DSB) within the genome in the presence and absence of the BLOOM protein. Zinc Finger Nucleases introduce DSBs at specified loci within the genome. Using sequencing we will assess the size of the deletion following repair. Protocol 1. Transfect normal and BLOOM deficient human iPS cells with ZFNs, using AMXA 2. Harvest cells after 5 days 3. Perform column extraction of DNA 4. PCR-amplify the ZFN region 5. Sequence and analyse repair of the DSB 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/

  Dataset EGAD00001000819

• DPY30 ChIP-seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57-66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176-85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).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/

  Dataset EGAD00001001268

• Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia - RNA

  Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 51/52 cases, this includes an established subtype defining genetic alteration in 5/52 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41).  Complex karyotype by cytogenetics emerges as a heterogeneous group, underlied by distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGK::BCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL.

  Dataset EGAD00001009305

• The patterns and dynamics of genomic instability in metastatic pancreatic cancer

  Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97–98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2–M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.

  Study EGAS00000000064

• National Institute on Alcohol Abuse and Alcoholism (NIAAA) Postmortem Prefrontal Cortex eQTL and mQTL Study

  Mapping expression and methylation quantitative trait loci (eQTLs and mQTLs) using genome-wide genotype, transcriptome, and DNA methylome data can provide an unbiased approach to identify novel functional variants. One critical issue of the eQTL/mQTL analysis is that the role of genetic variants in regulating gene expression (or DNA methylation) can be tissue- or cell-specific. To unravel causal variants from disease-associated loci, it would be necessary to map eQTLs and mQTLs in both patients and controls. Those eQTLs and mQTLs in patients are more likely to be causal variants for the disease. Identification of disease- and tissue-specific eQTLs and mQTLs will help disentangle the role of the specific tissue in disease development as well. In the present study, we mapped eQTLs and mQTLs in postmortem prefrontal cortex of patients with alcoholism or alcohol use disorder (AUD) and matched control subjects by integrative analyses of genome-wide SNP genotype, mRNA transcriptome, and DNA methylome data. As AUD is comorbid with schizophrenia (SCZ), bipolar disorder (BIP), major depressive disorder (MDD), and attention deficit/hyperactivity disorder (ADHD), we further examined the co-localization of PFC eQTLs/mQTLs and GWAS-identified SNPs (mainly noncoding SNPs) that were associated with AUD as well as comorbid SCZ, BIP, MDD, and ADHD. Our study demonstrated the enrichment of PFC eQTLs/mQTLs in the above psychiatric disorder-associated genetic variants identified by genome-wide association studies (GWAS).

  Study phs001981

• Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia

  Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile as well as a high rate of induction failure. Frequent mutations in cytokine receptor and JAK/STAT signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to IL7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6/6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pre-treatment levels and compared to control (P<0.01) in 5/6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P<0.01) in 6/6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed.

  Study EGAS00001001146

• RRBS sequencing of 7 tumour regions and a normal sample from a single TRACERx patient.

  Background: Epigenetic heterogeneity within a tumour can play an important role in tumour evolution and the emergence of resistance to treatment. It is increasingly recognised that the study of DNA methylation (DNAm) patterns along the genome - so-called `epialleles' - offers greater insight into epigenetic dynamics than conventional analyses which examine DNAm marks individually. Results: We have developed a Bayesian model to infer which epialleles are present in multiple regions of the same tumour. We apply our method to reduced representation bisulfite sequencing (RRBS) data from multiple regions of one lung cancer tumour and a matched normal sample. The model borrows information from all tumour regions to leverage greater statistical power. The total number of epialleles, the epiallele DNAm patterns, and a noise hyperparameter are all automatically inferred from the data. Uncertainty as to which epiallele an observed sequencing read originated from is explicitly incorporated by marginalising over the appropriate posterior densities. The degree to which tumour samples are contaminated with normal tissue can be estimated and corrected for. By tracing the distribution of epialleles throughout the tumour we can infer the phylogenetic history of the tumour, identify epialleles that differ between normal and cancer tissue, and define a measure of global epigenetic disorder. Conclusions: Detection and comparison of epialleles within multiple tumour regions enables phylogenetic analyses, identification of differentially expressed epialleles, and provides a measure of epigenetic heterogeneity.

  Study EGAS00001002484

• Atypical B cells and impaired SARS-CoV-2 neutralisation following heterologous vaccination in the elderly

  Age is a major risk factor for hospitalization and death after SARS-CoV-2 infection, even in vaccinees. Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here we show that individuals 70 or older who received a primary two dose schedule with AZD1222 and booster third dose with mRNA vaccine achieved significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared to those below 70 at one month post booster. Neither the concentration of serum binding anti spike IgG antibody, nor the frequency of spike- specific B cells showed differences by age grouping. Impaired neutralization potency and breadth post-third dose in the elderly was associated with enrichment of circulating “atypical” spike-specific B cells expressing CD11c and FCRL5. Presence of these atypical B cells was confirmed by scRNA seq. However, when considering individuals who received three doses of mRNA vaccine, we did not observe statistically significant differences in neutralization or enrichment in atypical B cells by age grouping following dose 3. Together, our data reveal impaired neutralising antibody responses in the elderly after heterologous vaccination with AdV followed by mRNA booster dose, but not in homologous three dose mRNA vaccination highlighting that different vaccine formats differentially instruct the memory B cell response.

  Study EGAS00001007385