16490 results for "sec+and+unspecified+malignant+neoplasm"

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• Identification of Genomic Markers of Cervical Dystonia and Subtypes

  As the third most common movement disorder, dystonias collectively affect more than 2 million people worldwide. Despite their high prevalence, their biological roots are largely unknown. Genetic influences are suggested in familial studies, however, no specific genetic variants are responsible for a significant proportion of identified cases. Previous genome-wide association studies of the dystonias were limited by smaller sample size and lack of coverage of rare variants. In this study, we use a high-throughput genomic approach to effectively investigate relationships between over genome-wide genetic variations and dystonias. We conduct targeted analyses of candidate genes, as well as agnostic searches for any genomic with the dystonias and subtypes in a large sample of dystonia patients available.

  Study phs001803

• Multi-Modal Single-Cell and Whole-Genome Sequencing of Small, Frozen Clinical Specimens

  Clinical application of single-cell sequencing technologies has been hampered by their need for quick processing of relatively large, fresh specimens. Here, we benchmarked the performance of a new technique for single-cell sequencing from snap-frozen clinical samples, vs. sequencing from fresh samples, on 5 samples from cutaneous melanoma brain metastasis, 6 samples from NSCLC brain metastasis, and 3 from uveal melanoma primary tumor. Additionally, we performed frozen sample sequencing of 20 uveal melanoma liver metastasis samples, and 3 cutaneous melanoma extracranial metastasis samples. Finally, for selected groups of the above-mentioned samples, we also performed TCR sequencing, SlideSeqV2 spatial transcriptomics, ultra-shallow whole-genome sequencing, and whole-exome sequencing, to present a comprehensive multi-modal profiling of all datasets.

  Study phs003097

• Tracing tumor evolution and heterogeneity of pleomorphic carcinoma of the lung

  Pulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous non-small-cell lung carcinoma whose underlying biology is still poorly understood. Forty-two tumor areas including 39 primary tumors and 3 metastases from 20 PPC patients were microdissected and the histologically distinct components were subjected to whole exome sequencing (WES) separately. Twenty non-tumor areas from matched PPC patients were also subjected to WES. Twist Human Core Exome + RefSeq + Mito-Panel kit (Twist Bioscience) was used for the whole exome capturing according to manufacturer’s guidelines. Paired-end 100-bp reads were generated on the Illumina NovaSeq 6000. After the sequencing, reads were aligned against the reference human genome GRCh38 using Burrows-Wheeler Aligner (BWA, v0.7.12)

  Study EGAS50000000314

• Transcriptome analysis of human longitudinal whole blood samples from PCR-positive and PCR-negative adults following controlled inoculation with Influenza A (H3N2) virus.

  Transcriptome analysis of influenza A (H3N2) human challenge samples. Understanding of the transcriptomic profile of individuals in early influenza infection is limited. To investigate this, longitudinal whole-blood samples (n=178) were taken from adult participants following controlled inoculation with Influenza A H3N2 virus (sampling at baseline (0) and days 1, 2, 3, 7, 10 and 14 post-challenge). Most participants became influenza PCR-positive; a minority remained PCR-negative. Total RNA was extracted from PAXgene tubes before undergoing globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced using Illumina NovaSeq 6000.

  Study EGAS50000000679

• Association studies using the Metabochip array - Samples analysed by the WTCCC (1958 British Birth Cohort (58BC), Hypertension cohort (HT), Type 2 Diabetes Cohort (T2D) and Coronary Artery Disease (CAD) cohort)

  Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have only at best identified moderate proportions of the genetic variants contributing to disease heritability. To provide cost-effective genotyping of common and rare variants to map the remaining heritability and to fine-map established loci, the Metabochip Consortium has developed a 200,000 SNP chip that has been produced in very large numbers for a fraction of the cost of GWAS chips. This chip provides a powerful tool for genetic studies of metabolic, cardiovascular and anthropometric traits (Voight et al., in press PLoS Genetics).

  Study EGAS00000000115

• Prostate Cancer and Normal Adjacent Prostate RNA-seq samples, NGS-ProToCol

  The dataset "Prostate Cancer and Normal Adjacent Prostate RNA-seq samples, NGS-ProToCol" includes 41 Normal Adjacent Prostate and 51 ribo-depleted Prostate Cancer RNA-seq samples. ---- Detection of fusion transcripts and their genomic breakpoints from RNA sequencing data Youri Hoogstrate, Malgorzata A. Komor, René Böttcher, Job van Riet, Harmen J. G. van de Werken, Stef van Lieshout, Ralf Hoffmann, Evert van den Broek, Anne S. Bolijn, Natasja Dits, Daoud Sie, David van der Meer, Floor Pepers, Chris H. Bangma, Geert J. L. H. van Leenders, Marcel Smid, Pim French, John W.M. Martens, Wilbert van Workum, Peter J. van der Spek, Bart Janssen, Eric Caldenhoven, Christian Rausch, Mark de Jong, Andrew P. Stubbs, Gerrit A. Meijer, Remond J.A. Fijneman, Guido Jenster

  Study EGAS00001002816

• Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

  We examined pre-treatment tumors from participants of the IMmotion150 trial. Biomarker analyses indicate that high angiogenesis gene expression was associated with improved PFS within the sunitinib arm, and high T-effector/IFNγ response (Teff) gene expression with longer PFS in atezolizumab + bevacizumab vs sunitinib patients. In high Teff tumors, concomitant high myeloid inflammation was associated with worse PFS in the atezolizumab monotherapy arm; adding bevacizumab to atezolizumab in this subgroup improved PFS vs atezolizumab. Molecular profiles suggest that prediction of outcomes with VEGF inhibitors and immunotherapy may be possible in mRCC, and bevacizumab may overcome myeloid inflammation-associated atezolizumab resistance.

  Study EGAS00001002928

• Mitochondrial DNA sequencing of iPSC, parental cells, and iPSC derived cardiomyocytes

  The aim of this work was to analyze to which extent mitochondrial DNA (mtDNA) variants in human induced pluripotent stem cells (iPSC) originate from their parental cells or from de novo mutagenesis, and whether dynamics in variant heteroplasmy levels during prolonged expansion culture of iPSC are caused by inter- or intra-cellular selection or genetic drift. Hence, mtDNA of 26 early passage iPSC clones from, in total, 10 donors and the corresponding parental cell populations (here endothelial cells) were sequenced. Furthermore, 7 iPSC clones were expanded up to passage 50 and the change in variant heteroplasmy levels was monitored. Lastly, the effect of differentiation on the variant heteroplasmy levels was investigated during directed cardiomyocyte differentiation of 4 iPSC clones.

  Study EGAS00001005560

• MutWP1: CRUK Grand Challenge Mutographs of Cancer: pancreas (2019-04-03)

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute (Illumina HiSeqX, 40X and 20X depth respectively). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004893

• Using genetics to identify cell types and mechanisms underlying susceptibility to primary sclerosing cholangitis

  Primary sclerosing cholangitis (PSC) is a T-cell mediated, chronic inflammatory condition of the biliary tree that is strongly associated with inflammatory bowel disease. Genome-wide association studies have identified 22 non-HLA genetic risk variants associated PSC. Identifying the genes impacted by these variants has proven difficult as the majority lie in non-coding regions of the genome. Knowledge of the genes and biological pathways these non-coding variants are perturbing is vital to understanding the disease biology. One means of assessing the impact of non-coding variants within disease associated loci upon genes is via colocalisation with eQTL. Many eQTL are cell-type specific, requiring the analysis of disease relevant cell types to detect colocalisation. We have collected PSC-relevant T-cell-subtypes from the peripheral blood of PSC patients via fluorescence activated cell sorting in preparation for RNA sequencing and mapping of eQTL. Samples were collected at the Norfolk and Norwich University Hopital, for which local ethical approval has been granted. Lysed cell samples will be transferred to WTSI and DNA/RNA will be extracted from lysed cell samples by T143 before genotyping (DNA) and custom library preparation and sequencing (RNA). 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 EGAD00001011815

• Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small Cell Lung Cancer

  Tumor mutational burden (TMB) has emerged as a predictive biomarker of response to immune checkpoint inhibitors. Standardization of TMB measurement is essential for implementing diagnostic tools to guide treatment. Here we evaluate bioinformatic TMB analysis by whole exome sequencing (WES) in formalin-fixed, paraffin-embedded samples. In CheckMate 026, TMB was retrospectively assessed in 312 patients with non-small cell lung cancer (58% of the intent-to-treat population) who received first-line nivolumab treatment or chemotherapy. We examined the sensitivity of TMB assessment to bioinformatic filtering methods and assessed concordance between TMB data derived by WES and the FoundationOne CDx™ assay. TMB scores comprising synonymous, indel, frameshift, and nonsense mutations (all mutations) were 3.1-fold higher than data including missense mutations only, but values were highly correlated (Spearman’s r = 0.99). Scores from CheckMate 026 samples including missense mutations only were similar to those generated from data in The Cancer Genome Atlas, but those including all mutations were generally higher. Using databases for germline subtraction (instead of matched controls) showed a trend for race-dependent increases in TMB scores. Parameter variation can therefore impact TMB calculations, highlighting the need for standardization. Encouragingly, WES and FoundationOne CDx outputs were highly correlated (Spearman’s r = 0.90) and differences could be accounted for by empirical calibration, suggesting that reliable TMB assessment across assays, platforms and centers is achievable.

  Dataset EGAD00001005035

• Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

  The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel's team at Children's Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

  Study phs001339

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• High response rate to anti PD-1 therapy in desmoplastic melanoma

  Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

  Study phs001469

• An APOBEC Cytidine Deaminase Mutagenesis in Human Cancers

  Reprinted from Roberts et al. "An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers", Nature Genetics, 45:970-976, 2013, with permission of Nature Publishing Group: Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.

  Study phs000677

• Comprehensive Epigenetic Landscape of Rheumatoid Arthritis Fibroblast-Like Synoviocytes

  We characterized the epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes (FLS) compared with osteoarthritis FLS. Multiple technologies were used, including ChIP-seq to assay H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3, ATAC-seq for chromatin accessibility, the transcriptome by RNA-seq and whole genomic bisulfite sequencing for DNA methylation. Integrative analysis was performed using a novel unbiased method to identify regions of the genome that have similar epigenetic marks. The regions that distinguished RA and osteoarthritis cells were primarily located in active enhancers and promoters. The regions and genes identified included immunological pathways. In addition, some unexpected pathways, most notably "Huntington's Disease Signaling", were discovered. The Huntington's Disease pathway was biologically validated for Huntingtin-interacting protein-1, which regulated invasive behavior of FLS. For a complete description, see R. Ai et al., Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun 9, 1921 (2018). Sequencing data of study participants are available through dbGaP's Authorized Access portal, while analyses of the sequencing data may be obtained through NCBI's GEO portal under GSE112658.

  Study phs001615

• Multicenter Study of Hydroxyurea (MSH)

  This study aimed to determine whether or not treatment with hydroxyurea titrated to maximum tolerated doses would reduce the frequency of vaso-occlusive (painful) crises by at least 50% in 299 men and women between 18 and 50 years old with a diagnosis of sickle cell anemia by gel electrophoresis conducted by a Core Laboratory. A secondary objective investigated correlations of fetal hemoglobin (HbF) levels and other patient or treatment characteristics with the occurrence of vaso-occlusive (painful) crises, and the effect of treatment on the quality of life.This controlled trial made hydroxyurea the first drug of proven benefit in preventing vaso-occlusive pain crisis and acute chest syndrome caused by sickle cell disease, with additional findings including reduced mortality in adult patients taking hydroxyurea for frequent painful sickle cell episodes after 9 of years follow-up. No significant side-effects of hydroxyurea therapy were noted.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002348

• Whole Genome Association Study of Systemic Lupus Erythematosus

  The goal of this collaborative study was to identify new genetic risk factors for Systemic Lupus Erythematosus (SLE). To do this we conducted a genome-wide scan by combining the resources and expertise from a number of SLE researchers to establish a large sample set comprising 1311 SLE cases and 3340 controls. The SLE case samples were genotyped from the following collections: 338 subjects from the Autoimmune Biomarkers Collaborative Network (ABCoN), an NIH/NIAMS funded repository, 141 subjects from the Multiple Autoimmune Disease Genetics Consortium (MADGC), 613 subjects from the University of California San Francisco (UCSF) Lupus Genetics, and 335 subjects from the University of Pittsburgh Medical Center (UPMC), plus 8 samples collected at The Feinstein Institute for Medical Research. A total of 3583 control samples were examined in the association analyses. As part of this project, 1861 control samples were selected and then genotyped from the New York Cancer Project (NYCP), based on self-described ethnicity, gender and age. In addition, genotype data from 1722 control samples (all self-described North Americans of European descent) were obtained from the publicly available iControlDB database (http://www.illumina.com/pages.ilmn?ID=231).

  Study phs000122

• Nanobody-Tethered Transposition Allows for Multifactorial Chromatin Profiling at Single-Cell Resolution

  Chromatin states are functionally defined by a complex combination of histone modifications, transcription factor binding, DNA accessibility, and other factors. However, most current single-cell-resolution methods are unable to measure more than one aspect of chromatin state in a single experiment, limiting our ability to accurately measure chromatin states. Here we introduce nanobody-tethered transposition followed by sequencing (NTT-seq), a new assay capable of measuring the genome-wide presence of multiple histone modifications and protein-DNA binding sites at single-cell resolution. NTT-seq utilizes recombinant Tn5 transposase fused to a set of secondary nanobodies (nb). Each nb-Tn5 fusion protein specifically binds to different immunoglobulin-G antibodies, enabling a mixture of primary antibodies binding different epitopes to be used in a single experiment. We apply bulk- and single-cell NTT-seq to generate high-resolution multimodal maps of chromatin states in cell culture and cells of the human immune system, demonstrating the high accuracy and sensitivity of the method. We further extend NTT-seq to enable simultaneous profiling of cell-surface protein expression alongside multimodal chromatin states to study cells of the immune system.

  Study phs003068

• Methotrexate Clearance GWAS in Acute Lymphoblastic Leukemia (ALL) Patients

  We estimated the plasma clearance of methotrexate from 1279 acute lymphoblastic leukemia (ALL) patients treated on the Children Oncology Group 9904 and 9905 trials (http://clinicaltrials.gov/show/NCT00005585 and http://clinicaltrials.gov/show/NCT00005596). Patients received either a 24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose). Methotrexate clearance was lower in older children (p=7 x 10-7), females (p=2.7 x 10-4), and patients who received a delayed intensification phase (p=0.0022). In a genome-wide analysis, methotrexate clearance was associated with polymorphisms in the SLCO1B1 gene (p=2.1 x 10-11), which encodes for an organic anion transporter. This replicates findings using different schedules of high-dose methotrexate in ALL patients treated on St. Jude protocols. A combined meta-analysis yields a p-value of 5.7 x 10-19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056 (Trevino et al, PMID 19901119 and Ramsey et al, PMID 23233662). This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays.

  Study phs000637

• Efficacy of Bitter Taste Blockers on Flavor Acceptance in a Human Population

  The goal of this project is to determine variation in human bitter perception and the effectiveness of bitter blockers in individuals of different genotypes. The project is based on the parent project titled "Efficacy of bitter taste blockers on flavor acceptance in pediatric population", which addresses how bitter taste perception affects medication compliance. As a part of the parent project, mothers and their children were recruited from the general population of metropolitan Philadelphia through print and internet media as well as from a database of past research participants. Adults (mothers) were evaluated in the laboratory for bitter taste perception for a variety of "Generally Recognized As Safe" (GRAS) bitter compounds using the general Labeled Magnitude Scale (gLMS) which allows subjects to rate sensory intensity. Mothers were also evaluated for perception of the liquid formulation of the drug KaletraTM, a recommended 1st line treatment for infants with HIV infection, whose taste is rejected by some children and accepted well by others. DNA samples from mothers were genotyped as a part of this study to identify (1) novel genes associated with human bitter perception and (2) the ability of compounds to block bitterness.

  Study phs000839

• Resistance Development in Basal Cell Nevus Syndrome through the Basal to Squamous Transition

  While basal cell carcinomas (BCCs) arise from ectopic hedgehog pathway activation and can be treated with pathway inhibitors, sporadic BCCs display high resistance rates, while tumors arising in Gorlin syndrome patients with germline Patched (PTCH1) mutations are uniformly suppressed by inhibitor therapy. In rare cases, Gorlin syndrome patients on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. Here we report a case of a Smoothened inhibitor (SMOi)-resistant tumor arising in a Gorlin patient on suppressive SMOi for nearly a decade. Using a combination of multi-omics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMOi through the previously described basal to squamous cell carcinoma transition (BST). Intriguingly, through spatial whole exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as novel genetic suppressors of BST resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMOi for not only Gorlin syndrome but sporadic BCCs as well.

  Study phs003415

• Molecular Determinants of Esophageal Cancer in Tanzania

  We describe the genomic profiles of 61 esophageal squamous cell carcinoma (ESCC) cases from Tanzania and compare them to profiles from an existing cohort of ESCC cases from Malawi. We also provide a comparison to ESCC tumors in The Cancer Genome Atlas Program (TCGA). Despite a high burden of ESCC in Eastern Africa, investigations into the genomics in this region are nascent. This represents the largest comprehensive genomic analysis of ESCC from sub-Saharan Africa to date. We observed substantial transcriptional overlap with other squamous histologies via comparison with TCGA PanCan dataset. DNA analysis revealed known mutational patterns, both genome-wide as well as in genes known to be commonly mutated in ESCC. TP53 mutations were the most common somatic mutation in tumors from both Tanzania and Malawi but were detected at lower frequencies than previously reported in ESCC cases from other settings. In a combined analysis, two unique transcriptional clusters were identified: a proliferative/epithelial cluster and an invasive/migrative/mesenchymal cluster. Mutational signature analysis of the Tanzanian cohort revealed common signatures associated with aging and cytidine deaminase activity and an absence of signature 29, which was previously reported in the Malawi cohort.

  Study phs003217

• Whole-Exome Sequencing Study of Diabetic Nephropathy

  To identify rare variants of diabetic kidney disease (DKD), we conducted a whole-exome sequencing (WES) study. This study employed an extreme case–control design, which included a selection of the 593 most rapidly progressing DKD cases from the Chronic Renal Insufficiency Cohort (CRIC) Study (phs000524). In this two-stage WES study of DKD, participants with DKD from the CRIC were compared with control groups of participants without DKD from another cohort in the first stage. Suggestive signals identified in the first stage were confirmed in the second stage analysis among a diverse population with existing whole-genome sequencing (WGS) data. Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. As a result, we identified four novel gene loci, DIS3L2, KRT6B, ERAP2 and NPEPPS, that achieved exome-wide significance and may play an important role in the DKD disease course. This large WES study provides novel insights into DKD's molecular mechanisms.

  Study phs003429

• Mapping Disease Pathways for Biliary Atresia

  Biliary atresia (BA) is a poorly understood rare disease that causes jaundice and liver failure at birth due to underdeveloped bile ducts. Associated defects include poor development of the portal vein and involvement of non-hepatic organs. After initial surgical drainage in all patients, the majority need liver transplantation because of progressive cirrhosis. In addition to the risks of lifelong immunosuppression after liver transplantation, the post-transplant biliary atresia patient can experience surgical complications like portal vein thrombosis along with the consequences of extrahepatic involvement often found in affected patients. To determine the genetic basis of this disease, a genome-wide association study of 811 BA cases, all of whom received liver transplantation, and 4654 controls was performed with a 2.5 million SNP array. The study found that BA associates with polygenic risk conferred by over 6000 common variants, minor allele frequencies >1%, in 102 ciliogenesis and planar polarity effector genes (CPLANE). Whole genome sequencing of 100 of 811 cases revealed that most cases harbored rare variants, allele frequencies Whole genome genotyping, gene expression and whole genome sequencing data is being made available.

  Study phs003458