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• WES in HCCOs with varying Doxorubicin resistance

  We aimed to identify somatic mutations that could explain the resistance to Doxorubicin. Therefor, we purified Exomes from liver biopsies and HCC organoids using Agilent SureSelectXT (clinical research exome, HS2 V8, or Human all Exon V6 Cosmic) and performed WES. Matched non-tumoral liver biopsies served as the control for germline mutations. 12 of these samples were previously reported. Sequence reads were aligned to the reference human genome GRCh38 using Burrows-Wheeler Aligner (BWA, v0.7.17). Duplicate removal, base quality adjustment, mutation calling (Mutect2, intervals: SureSelectXT_HS_V8_S33266340, germline-recourse: gnomad.exomes.r2.1.1.sites.liftover_grch38, Panel-of-Normal: 1000g_pon.hg38), filtering of Mutect calls, and functional annotation (Funcotator, funcotator_dataSources.v1.7.20200521g) were performed using the Genome Analysis Toolkit (GATK, v4.4) according to the Broad Institute best practices in Somatic short variant discovery workflows. Mutations with a functional annotation of Deletion, Insertion, Non-stop, Splice-Site, Start-Codon and Missense mutations were kept. A list of 43 commonly mutated genes in HCC was analyzed in the HCC organoids [TCGA, Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell, 2017. 169(7): p. 1327-1341.e23].

  Study EGAS50000000043

• Systemic Inflammation and Lymphocyte Activation Precede Rheumatoid Arthritis

  The Allen Institute for Immunology-University of California, San Diego-University of Colorado Transition to Rheumatoid Arthritis (ALTRA) project is a prospective longitudinal cohort study to understand the pre-clinical development of rheumatoid arthritis (RA). We performed cross-sectional and longitudinal multi-omics analyses of peripheral immunity in the anti-citrullinated protein autoantibody-positive (ACPA+) at-risk for RA period. We provide FASTQ files from (1) single-cell RNA sequencing (scRNA-seq) of ACPA+ at-risk (n=45), ACPA+ early RA (n=11), and site-matched ACPA- controls (n=38); (2) scRNA-seq of longitudinal samples from ACPA+ at-risk who developed clinically active RA during our study (n=16 participants, n=75 samples) and ACPA- controls (n=29 subjects, n=89 samples); (3) trimodal TEA-seq of a subset of ACPA+ at-risk (n=7) and ACPA- controls (n=5). Using these data, we characterize pathogenesis prior to clinical RA diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity.

  Study phs003944

• Recursive splicing in long vertebrate genes

  Recent studies have shown that expression of many genes with exceptionally long introns in the mammalian brain can be perturbed by regulatory factors linked to neurodevelopmental or neurodegenerative disorders1-3, suggesting unique regulatory mechanisms. Here we identify functional recursive splice sites (RSS) in long introns of genes expressed in the brain. These RSS are highly conserved in genes with extreme length across diverse vertebrate species and permit step-wise removal of long introns via recursive splicing. Recursive splicing requires initial definition of a “recursive exon” that is located downstream of RSS, and most often contains premature stop codons. Moreover, we show that RSS create a splicing switch driven by splice site competition in order to distinguish primary mRNA isoforms from alternative isoforms that are prevalent in long genes. The recursive exon is not detectable in the dominant mRNA isoform due to recursive splicing, but is completely included when cryptic promoters or other cryptic exons are used. Thus, by coupling inclusion of recursive exons with the use of cryptic elements, RSS act to distinguish new mRNA isoforms emerging from long genes.

  Study EGAS00001001170

• Exome-seq, RNA-Seq, SNP array profiling of gastric tumor samples and cell lines.

  Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we performed exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumors and 32 cell lines. Meta-analysis of the exome data and previously published data sets revealed 24 significantly mutated genes in MSS tumors, and 16 in MSI tumors. More than half of the patients in our collection could potentially benefit from targeted therapies. We identified 55 splice-site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumors. The ZAK kinase isoform TV1 is preferentially upregulated in gastric tumors and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder, and breast cancers. Overexpression of this particular isoform activated multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibited proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK.

  Study EGAS00001000736

• Epigenetic and metabolomic data from type 2 diabetes adolescents

  Objective: Rates of type 2 diabetes (T2D) among adolescents are on the rise. Epigenetic changes could be associated with the metabolic alterations in adolescents with T2D. Methods: We performed a cross-sectional integrated analysis of DNA methylation data from peripheral blood mononuclear cells with serum metabolomic data from First Nation adolescents with T2D and controls participating in the Improving Renal Complications in Adolescents with type 2 diabetes through REsearch (iCARE) cohort study, to explore the molecular changes in adolescents with T2D. Results: Our analysis showed that 43 serum metabolites and 36 differentially methylated regions (DMR) were associated with T2D. Several DMRs were located near the transcriptional start site of genes with established roles in metabolic disease and associated with altered serum metabolites (e.g. glucose, leucine, and gamma-glutamylisoleucine). These included the free fatty acid receptor-1 (FFAR1), upstream transcription factor-2 (USF2), and tumor necrosis factor-related protein-9 (C1QTNF9), among others. Conclusions: We identified DMRs and metabolites that merit further investigation to determine their significance in controlling gene expression and metabolism which could define T2D risk in adolescents.

  Study EGAS00001003816

• An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

  In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.

  Study EGAS00001004839

• An Isogenic Cell Line Panel for Sequence-based Screening of Targeted Anti-cancer Drugs

  We describe the creation and characterization of an isogenic cell line panel representing common cancer pathways, with multiple features optimized for high-throughput screening. More than 1,800 cell lines from three normal human cells were generated using CRISPR-technologies. Surprisingly, we discovered most of these lines did not result in complete gene inactivation, despite integration of sgRNA at the desired genomic site. However, a subset of the lines harbored true, biallelic disruptions of the targeted tumor suppressor gene, yielding a final panel of 100 well-characterize lines covering 19 pathways frequently subject to loss of function in cancers. This panel included genetic markers optimized for sequence-based ratiometric assays for drug-based screening assays. To illustrate the potential utility of this panel, we developed a multiplexed high-throughput screen that identified Wee1 inhibitor MK-1775 as a selective growth inhibitor of cells with inactivation of TP53. These cell lines and screening approach should prove useful for researchers studying a variety of cellular and biochemical phenomena

  Study EGAS00001005974

• Genomic analysis and evolutionary modeling of breast and larynx cancer, based on specimens from Polish population

  We explore the genomic characteristics of the original dataset of breast and larynx cancer specimens of several cell types from the collection of the Department of Applied Radiology of the Maria Sklodowska-Curie National Research Institute of Oncology, Krakow (Poland) Branch and Institute of Human Genetics Polish Academy of Sciences. DNA from paired tissue samples from primary tumor locations and concurrent metastasis to regional lymph nodes was sequenced and matched to controls. A range of genomic analyses was carried out, such as estimation of variant allele frequencies (VAF) and copy number variation (CNV). They show that subsets of variants from primary tumors are present in metastatic lymph nodes and that the CNV pattern is similar, but not identical to that known in the literature. In addition to that, we fit the VAF data to theoretical site frequency spectra predicted by multiple models found in the literature. Analysis suggests existence of secondary advantageous subclones arising on the clonal background as well as of a number of neutral or slightly deleterious passenger mutations.

  Study EGAS00001006456

• The Mutational Landscape of CTCL and Sezary Syndrome

  Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

  Study phs000994

• Genetics of Glucose Regulation in Gestation and Growth (Gen3G) Cohort - Placenta Transcriptomics RNA Sequencing

  The overarching goals of Genetics of Glucose regulation in Gestation and Growth (Gen3G) are to increase our understanding of biological, environmental, and genetic determinants of glucose regulation during pregnancy and their impact on fetal/child development. Gen3G is a prospective cohort study: we initially recruited 1,024 pregnant women between 2010-2013 at Blood Sampling in Pregnancy Clinic during the first trimester of pregnancy (median 9 weeks of gestation) in Sherbrooke, Québec, Canada. We assessed 898 pregnant women at second trimester (median 26 weeks of gestation), when participants completed a 75g oral glucose tolerance test (OGTT) as clinically indicated for screening of gestational diabetes mellitus (GDM). We collected data for 854 mother-child dyads at delivery (from medical records), in addition to placenta and/or cord blood samples in majority of newborns.The overall goal of the grant that supported data that is included in this dbGaP submission was to discover novel placental factors that regulate glucose metabolism in pregnancy and predict GDM by conducting genome-wide transcriptomics (RNA and miRNA) in carefully collected placenta samples from Gen3G.

  Study phs003151