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• H3Africa - Kidney Disease Research Network

  Chronic kidney disease (CKD) affects an estimated 14% of adults in sub-Saharan Africa but very little research has been done on the etiology, progression and prevention of CKD on the continent. As part of the Human Heredity and Health in Africa (H3A) Consortium, the H3Africa Kidney Disease Research Network was established to study prevalent forms of kidney disease in sub-Saharan Africa and increase the capacity for genetics and genomics research. The study is performing comprehensive phenotypic characterization with analysis of environmental and genetic factors from seven clinical centers in two African countries (Ghana and Nigeria) over a five-year period. Approximately 4,000 participants with specified kidney disease diagnoses and 4000 control participants will be enrolled in the four African countries. In addition, approximately 50 families with hereditary glomerular disease will be enrolled. The study includes both pediatric and adult participants ages <1 to 74yrs across a broad spectrum of kidney diseases secondary to hypertension, diabetes, human immunodeficiency virus, sickle cell disease, biopsy-proven glomerular disease and CKD of unknown origin. Clinical and demographic data with biospecimens are collected for assessment of clinical, biochemical and genetic markers of kidney disease.

  Study EGAS00001006558

• Immunogenetics of BCG Vaccination and Pediatric Tuberculosis

  We examined genetic variation associated with BCG-induced innate immune responses and susceptibility to pediatric tuberculosis (TB) disease. South African study participants were enrolled at the South African Tuberculosis Vaccine Initiative (SATVI) as part of a larger BCG vaccination study. This area has one of the highest rates of TB incidence in the world. Infants were vaccinated with BCG at birth, and a nested case-control study was performed over a 2-year prospective observation period, which resulted in 135 infant TB cases and 521 controls. Whole blood was collected from BCG vaccinated infants at 10 weeks of age. Genotyping was performed with the llumina MegaEx Beadchip, and GWAS was performed against TB disease to assess for associations between genetic variants and susceptibility to TB. In addition, a subset of infants were assessed for BCG-induced innate immune responses (N=198). For these, whole blood was stimulated with BCG or media and flow cytometry was used to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. Cellular GWAS was then performed to associate genetic variants with BCG-induced immune responses.

  Study phs003406

• Genomics characterization of primary central nervous system lymphoma

  Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS). Despite low tendency of systemic dissemination, its prognosis is poor with median overall survival of 2?4 years. Due to its rarity, knowledge of genomic alterations underling PCNSL pathogenesis is severely limited. Here we performed whole-exome sequencing on 44 PCNSL and paired normal specimens, revealing high penetrance of nonsynonymous somatic mutations in PIM1 (95.5%), BTG2 (88.6%) and MYD88 (81.8%). Interestingly we found oncogenic mutations in GRB2, and this effect was cancelled when transformed cells are treated with inhibitors to downstream kinases MAP2K1/2. Further, when tumor cells carries MYD88 mutations, the same mutations were also found at low frequency in peripheral blood mononuclear cells (PBMNC), implying that MYD88 mutation?positive precancerous cells originate outside CNS and develop to lymphoma with additional genetic hits that fit the CNS environment.

  Study JGAS000021

• Shedding light over COVID-19 susceptibility and severity

  “One of the most remarkable features of SARS-CoV-2 infection is the variation in consequence ranging from asymptomatic to life-threatening” state the authors of the majestic Nature paper released in accelerated pre-view on July 2021. This variation in consequences represent not only an issue of burning medical relevance, but also a scientific and intellectual challenge for scientists around the globe. Researchers are known to be easily triggered by a challenge, and they recently demonstrated to be even better at double their efforts to focus on an urgent societal need. In this work led and coordinated by the COVID-19 Host Genetics Initiative (COVID-19 HGI), researchers gathered data from 49,562 cases and two million controls from 46 studies performed worldwide. The majority of the data has been deposited at the EGA, where 29 datasets have been collected under the study number EGAS00001005304. Data gathered from diverse sources conferred a huge robustness to the results. Genetic data from different ancestry origin were included in the analyses, even though data from patients with European origin was highly predominant (approx. 75%). Separated analysis of the different ancestries gave rise to relevant differences in the results, highlighting how important it is to take this aspect in consideration for future studies. Data from the individual studies was compiled into three categories according to COVID-19 severity for a meta-analysis: (a) critically ill cases (b) moderate or severe cases (c) all cases. They were paired with non-COVID-19-reported controls. All three analysis resulted in a total of 13 genetic loci associated with COVID-19 severity. Out of those, 9 loci associated specifically with critical illness, while 6 (a few overlapped) associated with moderated illness. Some genomic position matched previous findings. Interestingly, working with such an enormous amount of data allowed the depth to discriminate association with disease susceptibility vs severity, an issue of large medical relevance. Several loci mapped into biological relevant genes, like TYK2, PPP1R15A and FOXP4, previously implicated in immune response and/or lung functions. Researchers participating in the COVID-19 Host Genetics Initiative have worked in an unprecedented time-tight collaboration, prioritizing data sharing and collective results to tackle the pandemic affecting the world. The scientific community won’t miss any of the lessons to learn from this, and the EGA is ready to keep working to enable safe data sharing and fruitful collaborations.

  Blog covid-19-susceptibility-and-severity

• Dynamics of multiple resistance mechanisms in plasma DNA and their clinical implications for NSCLC patients receiving EGFR-targeted therapies

  Background:The development of resistance mechanisms to targeted therapies is complicated by underlying tumour heterogeneity. When multiple resistance mechanisms co-exist, identifying the dominant driver(s) is critical for selection of treatment. Patients and methods:We studied the relative dynamics of multiple oncogenic drivers and resistance mechanisms in 50 patients with EGFR-mutant non-small cell lung cancer (NSCLC), during treatment with gefitinib and hydroxychloroquine (NCT00809237). We performed digital PCR and targeted deep sequencing of cell-free DNA from longitudinal plasma samples from all patients, and shallow whole genome sequencing of serial samples from three patients who underwent histological transformation to small-cell lung cancer (SCLC). ResultsEGFR activating mutations were assessed in tumour samples and accurately identified in plasma samples of 95% of patients (41/43). We identified additional mutations including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%), and PTEN (4/50, 8%), and tracked their relative levels in plasma. Patients with both TP53 and EGFR mutations detected in plasma pre-treatment tended to have worse overall survival than those where only EGFR was detected. The resistance-conferring EGFR T790M mutation was identified in 62% of the patients who progressed. Changes in relative levels of T790M and activating mutations in EGFR corresponded to clinical responses in two patients who were given sequential treatments. Patients who progressed without T790M detected in plasma had worse PFS during TKI continuation, and developed alternative resistance mechanisms, that could be identified in plasma DNA, including SCLC-associated copy number changes and TP53 mutations, that tracked with progression and response to subsequent therapies. Conclusion:Longitudinal analysis of multiple oncogenic drivers in ctDNA may help identifying dominant mechanisms of resistance to EGFR-targeted therapies, and highlight the importance of monitoring genetic events that are not direct drug targets but provide non-invasive molecular information that may guide clinical management.

  Study EGAS00001002908

• Pathways Study

  The Pathways Study (NCI R01 CA105274, PI: Kushi), is a prospective cohort study of a diverse population of recently diagnosed breast cancer survivors in KPNC. The aims are to examine the effect on recurrence and survival of 1) lifestyle factors such as diet, physical activity, and use of complementary and alternative therapies and 2) molecular factors such as biomarkers of inflammation and tumor DNA methylation profiles. Recruitment into the cohort was from January 2006 to May 2013. Baseline data collection was by in-person interview (on average two months post-diagnosis), with follow-up via mailed or phone questionnaires at 6, 24, and 72 months and outcomes and comorbidities at 12, 24, 48, 72, and 96 months post-enrollment. The Pathways Study is now funded through May 2021 as a cancer cohort infrastructure grant (U01 CA195565, MPI: Kushi/Ambrosone). The Pathways baseline interview consists of interviewer- and self-administered questionnaires. Interviewer-administered questionnaires collected information including demographics, family health history, pregnancy health history, menstrual history, history of breast care screening procedures, smoking history, hormone use, medication history, and vitamin and mineral use. Self-administered questionnaires collected information on diet, physical activity, CAM use, lymphedema, and psychosocial and quality of life measures.

  Study phs001534

• Illumina GSA-MD v3 genotyping arrays for 183 samples

  Genotyping arrays for 183 samples from patients with a neuroendocrine tumor of the small intestine. All samples have been hybridized on Illumina GSA-MD v3 arrays with standard automated protocols. Reading of the chips was performed on Illumina iScan+ scanners and this file is the result of primary analysis done using Illumina GenomeStudio software. It contains data for 147 tumors, 2 adenomas, 1 lymph node, 19 mesenteric nodules, 6 liver metastasis and 8 normal ileum samples.

  Dataset EGAD50000000905

• Genetic Factors associated with Conversion from Active Surveillance to Treatment for Prostate Cancer

  This is a genome-wide association study (GWAS) of conversion from active surveillance (AS) for prostate cancer (PC) to treatment. AS is the monitoring with screening tests and/or biopsies over time of men usually with low-risk, early-stage PC to avoid harmful side effects of PC treatment. "Conversion" refers to patients who withdraw from AS (switch to active treatment) due to changes in their cancer development, anxiety about delayed treatment, or other reasons. Patients who converted because of anxiety alone were censored in the GWAS analysis. The overall goal of this study is to develop an easily measurable, germline-based panel of genetic variants to aid in selecting PC patients appropriate for AS and/or the intensity of monitoring. In total, 6,324 PC patients from 28 collaborating institutions are included in this study. Patients are those with PC who are either on AS or who have previously converted from AS to treatment. In this study, 70% of all subjects were diagnosed with very low-risk, low-risk, or low-volume intermediate-risk PC (Kryvenko and Epstein, 2016; PMID: 26709152) and have been enrolled in an AS program. DNA was extracted from blood, saliva, or formalin-fixed, paraffin-embedded (FFPE) tissue collected from the study subjects at the participating sites. Genotyping, quality control processes, and imputation were performed at the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. CIDR used the Illumina Infinium Multi-Ethnic Global Array (MEGA) version 1, which included genome-wide tag SNPs and 10,000 SNPs selected with custom content. Quality control and assurance (QC/QA) checks on genotyped data involved four domains: sample-level checks, batch effects, SNP-level checks, and preliminary association tests. Samples and SNPs passing the QC/QA checks were imputed to appropriate reference panels (HRC r1.1 for patients of European ancestry) using the Michigan Imputation Server (PMID: 27571263). Unmeasured genetic variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) Imputation Server, with 97,256 reference samples and 308,107,085 SNPs. Variants with imputation quality (INFO) score < 0.3 were excluded, leaving a total of 22,691,641 SNPs successfully imputed. After QC steps, a total of 5,936 samples genotyped at CIDR remained for inclusion in the GWAS.

  Study phs002056

• Tumour evolvability metrics predict recurrence in advanced localised prostate cancer (tumour data)

  There is a need for quantitative measurements of evolutionary metrics in controlled clinical trials with long term follow-up information. This is particularly true in advanced localised prostate cancer, which can recur more than a decade after diagnosis. Here we mapped genomic intra-tumour heterogeneity in 642 tumour samples from 114 patients who took part in the IMRT and DELINEATE clinical trials, for which full clinical information and 12y median follow-up was available. We concomitantly assessed phenotypic (morphological) heterogeneity using Deep Learning in 1,923 histological sections from 250 IMRT patients (fully overlapping with the genetic set). This study shows that combining genomics with AI-aided histopathology in clinical trials leads to novel clinical biomarkers. This EGA repository contains data produced from tumour samples using low coverage whole genome sequencing and a prostate cancer specific gene panel data following compression of unique molecular identifiers.

  Dataset EGAD00001010274

• Tumour evolvability metrics predict recurrence in advanced localised prostate cancer (normal data)

  There is a need for quantitative measurements of evolutionary metrics in controlled clinical trials with long term follow-up information. This is particularly true in advanced localised prostate cancer, which can recur more than a decade after diagnosis. Here we mapped genomic intra-tumour heterogeneity in 642 tumour samples from 114 patients who took part in the IMRT and DELINEATE clinical trials, for which full clinical information and 12y median follow-up was available. We concomitantly assessed phenotypic (morphological) heterogeneity using Deep Learning in 1,923 histological sections from 250 IMRT patients (fully overlapping with the genetic set). This study shows that combining genomics with AI-aided histopathology in clinical trials leads to novel clinical biomarkers. This EGA repository contains data produced from tumour samples using low coverage whole genome sequencing and a prostate cancer specific gene panel data following compression of unique molecular identifiers.

  Dataset EGAD00001010295

• Methylation Profiles of Cell-Free DNA Using Nanopore Sequencing

  Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to hundreds of millions of reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.Control subjects consist of healthy individuals without a positive diagnosis of cancer. cfDNA was obtained through purification of plasma from blood draws. Genomic DNA (gDNA) was derived from extraction of primary tumor tissue or from leukocytes from blood draws.

  Study phs002950

• Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

  In this study, the genomic landscape of extracutaneous juvenile xanthogranuloma (JXG) was analyzed. By leveraging the Dutch Nationwide Pathology Databank (Palga), tumor samples were obtained from different academic medical centers in the Netherlands. The study was approved by the Palga Scientific Council and Privacy Committee (LZV-2016-183) and the Institutional Review Board of Leiden University Medical Center (B19.074). In addition, the study was approved by the Biobank and Data Access Committee of the Princess Máxima Center for Pediatric Oncology (PMCLAB2024.0512). Provided are whole transcriptome sequencing (WTS) data of 3 histiocytic tumors with CLTC::SYK fusions. WTS was performed in the routine workflow of the Princess Máxima Center for Pediatric Oncology (as described in Hehir-Kwa, et al. JCO Precis Oncol 2022). RNA was derived from formalin-fixed paraffin-embedded tumor tissue (n=1) or from frozen tumor tissue (n=2).

  Study EGAS50000000584

• Tenk10k Phase 1: Whole Genome Sequencing

  TenK10K Phase 1 is a dataset of matched human whole-genome sequencing (WGS) from 1,925 individuals, and single-cell RNA sequencing (scRNA-seq) from over 5 million peripheral blood mononuclear cells across 28 immune cell types. Single-cell ATAC sequencing was additionally performed on a subset of 922 individuals. This EGA study consists of the WGS data from 1,925 individuals while a separate EGA study comprises the scRNA-seq and scATAC-seq data.

  Study EGAS50000001654

• Discrepancies in Tumour Mutation Burden (TMB) reporting from sequential Endobronchial ultrasound trans bronchial needle aspiration (EBUS TBNA) samples within single lymph node stations

  Introduction: Tumour Mutation Burden (TMB) is a potential biomarker for immune therapies. Identifying factors that may affect TMB prediction is key to its utility as biomarker for treatment options. Here we investigated parameters that might affect TMB using cytology smears obtained from endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA)-sampled malignant lymph nodes, which are often the only diagnostic samples collected in patients with advanced lung cancer. Methods: Individual Diff-Quik cytology smears were prepared for each needle pass from the same enlarged malignant mediastinal lymph nodes. DNA extracted from smears of each pass underwent sequencing using a large gene panel sequencing (TSO500, Illumina). TMB was estimated for each individual needle pass using the TSO500 Local App v. 2.0 (Illumina). Results: Twenty patients had two or more Diff-Quik smears (total 45 smears) which passed sequencing quality control. Average TMB for all smears was 8.7 ± 5.0 mutations per megabase (Mb). Sixteen of the 20 patients had paired samples with minimal differences in TMB score (average difference 1.3 ± 0.85). Paired samples from 13 patients had concordant TMB in terms of scores being below or above a threshold of 10 mutations/Mb. Samples from seven patients had discrepant TMB, with four cases in particular exhibiting an average difference of 11.3 ± 2.7 mutations/Mb. Factors affecting TMB calling involved tumour content of the samples, the amount of DNA used in sequencing as well as bone fide intra tumour heterogeneity between paired samples. Conclusions: TMB assessment is feasible from EBUS-TBNA derived Diff-Quik slides from a single needle pass. Repeated samples of one or more lymph nodes have minimal variation in TMB in most cases (80%), suggesting accuracy of the test overall. To enhance accuracy of the result, care should be taken in relation to the tumour content of the cytology smear. Further, clinicians should be aware that even slight differences in lymph node site selection could give rise to variable genomics and discrepant TMB due to tumour heterogeneity. Therefore, it would be reasonable for multi-lymph node site analysis of TMB to be performed using EBUS TBNA aspirates from different easily accessible lymph nodes. Further investigations need to determine whether these samples should be combined as one sample or tested separately.

  Study EGAS00001007484

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal

  he 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. 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.

  Study EGAS00001003774

• NRG-GY017: Atezolizumab before and/or with Chemoradiotherapy in Immune System Activation in Patients with Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer

  Locally advanced cervical cancer remains an area of high therapeutic unmet need, with ~50% of patients developing disease recurrence despite treatment with chemotherapy combined with radiation. Combination of immune checkpoint blockade with chemoradiation has been explored in this setting, but optimal sequencing of these modalities is unknown. To address this question, we developed and conducted the NCI sponsored trial “Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently with Extended Field Chemoradiotherapy for Node Positive Locally Advanced Cervical Cancer”, randomizing patients to atezolizumab administration prior to and concurrent with chemoradiation therapy (CRT) vs. concurrent with CRT (NRG-GY017; N=40, ClinicalTrials.gov Identifier: NCT03738228). Patients were randomized to atezolizumab neoadjuvant and concurrent (Arm A) or concurrent with CRT (Arm B). The study closed to successful accrual of 36 evaluable patients in June 2020. Out of 40 patients consented patients, 4 were never treated. The reasons for that are: 2 were screen failures, 1 withdrew consent, and 1 was not treated due to physician preference. The study incorporated comprehensive collection of pre- and on-treatment tumor biopsies as well as multitime point blood collections. T cell receptor (TCR) sequencing was performed on the tumors as well as pre- and on-treatment peripheral blood, and the data are included with dbGaP submission. Among the 36 eligible and treated patients, there were 30 (17 on Arm A and 13 on Arm B) with pre- and on-treatment peripheral TCR sequencing data. Twenty-five patients (14 in Arm A and 11 in Arm B) had additional tumor TCR sequencing data available, which enabled tracking of tumor-associated TCR clones in peripheral blood. We demonstrate that neoadjuvant atezolizumab administration results in peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B and is associated with favorable 2-year disease-free survival (DFS). No new safety signals were identified. These findings support further evaluation of the neoadjuvant IO and CRT sequencing strategy in locally advanced cervical cancer.

  Study phs003833

• Scottish High Grade Serous Ovarian Cancer

  Scottish HGSOC samples were collected via local Bioresource facilities at Edinburgh, Glasgow, Dundee and Aberdeen and stored in liquid Nitrogen until required. HGSOC patients were determined from pathology records and were included in the study where there was matched tumour and whole blood samples. On receipt of tumour material the tumour was processed as follows: firstly, the tumour sample was divided into two for DNA and RNA extraction. Slivers of tissue were cut from the front and rear faces of the DNA sample, then fixed in formalin and embedded in paraffin wax. Sections from the front and rear tissues from all samples were examined by H&E staining supplemented by WT1/p53 immunohistochemistry if required. Following pathology review, samples were only included if they met the following criteria: they were confirmed as HGSOC and there was greater than 40% tumour cellularity throughout the tumour, determined using the H&E sections. Somatic DNA was extracted using the Qiagen DNeasy Blood and tissue kit (cat no 69504). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including RNase digestion step). Germline DNA was extracted from 1-3ml whole blood using the Qiagen FlexiGene kit (cat no 51206) following the manufacturers recommended protocol. The resulting DNA underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as surrogate measures of DNA purity. A260/280 had to be 1.8 or greater and A260/230 had to be 2.0 or greater. Then, DNA was quantified using LifeTechnologies Qubit dsDNA BR kit (cat no Q32850) and we required a minimum of 50ul at 25ng/ul for WGS. Thirdly, DNA was diluted to 25ng/ul and a representative sample was loaded onto a 0.8% TAE gel, ran at 100v for 60mins and then imaged using a BioRad ChemiDoc imaging system to visualise the DNA quality. Only when all 4 quality control requirements were satisfied was the DNA sequenced. The DNA was sequenced at the Glasgow Precision Oncology Laboratories.

  Study EGAS00001004410

• Targeted sequencing of cell-free DNA and white blood cells from 24 men with metastatic prostate cancer

  This dataset consists of aligned DNA sequencing data in BAM file format from cell-free DNA and white blood cells from 24 men with metastatic prostate cancer. One cell-free DNA sample and one white blood cell sample is available for each patient, resulting in 48 total BAM files in this dataset. The sequencing was performed using a hybrid capture-based targeted panel of 73 prostate cancer driver genes.

  Dataset EGAD00001004486

• RNAseq data from the study - Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

  This study assessed molecular determinants of response in a cohort of patients with AML that were treated with venetoclax in combination with either DNA methyltransferase inhibitors or low dose cytarabine. RNA sequencing was performed on 31 patients from three different response classes [10 Group A - Durable remission (n=10), Group B - Relapsed (n=10) and Group C - Refractory (n=11)]. Library preparation and sequencing was performed at the Australian Genome Research Facility, using the Truseq Stranded mRNA library kit. Technical and batch replicate samples are included. Gene count data are provided with the original publication. The use of the sequencing data is subject to a data transfer agreement and is restricted to ethically approved research into blood cell malignancies and cannot be used to assess germline variants.

  Dataset EGAD00001005949

• Pre-diagnostic saliva microbiota of Finnish children with autoimmune diseases

  Pre-diagnostic saliva microbiota samples of Finnish children (aged 11/12 years). This is a case-control study, where case refers to the children who developed Type 1 DM or IBD later in life and control refers to the children who were free from these diseases. The aim of the study was to find biomarkers in saliva microbiota that may help us predict DM or IBD before the onset of these diseases.

  Study EGAS00001006949

• Estonian Biobank | Estonian Genome Center, University of Tartu

  The Estonian Biobank is the population-based biobank of the Estonian Genome Centre of University of Tartu. The biobank is conducted according to the Estonian Gene Research Act and all participants have signed broad informed consent. The cohort size is currently 51,535 people from 18 years of age and up. Metabolite concentrations (over 110; NMR and MS) are available for about 12,000 subjects; metabolic follow-up has been done for more than 2000 donors. GWAS has been performed on 20,000 subjects with different Illumina arrays and 2,500 have whole exomes and 2,400 full sequence. The data for the 2,400 fully sequenced samples is available through dbGaP.

  Study phs001230

• Genetic Components of Knee Osteoarthritis (GeCKO) Study: The Osteoarthritis Initiative

  The Osteoarthritis Initiative (OAI) is a publicly and privately funded prospective longitudinal cohort with a primary objective of identifying risk factors for incidence and progression of tibiofemoral knee OA. The OAI utilized a focused population-based recruitment to enroll 4,674 men and women between the ages of 45-79 years who either had radiographic symptomatic knee OA or who were without radiographic symptomatic OA in both knees but were considered high risk for OA because they had two or more known risk factors for knee OA. Subjects were recruited into the baseline phase of the OAI at multiple sites throughout the US between 2004 and 2006. All subjects were invited back for follow-up examinations to assess incidence or progression of OA annually, for up to 5 years. Phenotype data from the baseline and follow-up examinations are available for public access from the Osteoarthritis Initiative (OAI) database at http://www.oai.ucsf.edu/. The Genetic Components of Knee Osteoarthritis (GeCKO) Study was initiated in 2009 as a genetic ancillary study to perform a genome-wide association study to identify genetic variants associated with radiographic osteoarthritis. This study included 4,482 individuals participating in the parent OAI study. Following sample cleaning (e.g., removal of duplicates, sex mismatches, poor sample quality, etc.), the final sample set included 4,129 individuals.

  Study phs000955

• Molecular characteristics in Burkitt lymphoma over age groups

  Treatment optimization has improved the overall survival in Burkitt lymphoma (BL) patients but there are still relevant outcome differences between pediatric and adult patients. In both age groups survival remains poor for patients who suffer relapse. Therefore, new treatment approaches are warranted to improve survival. Thus, we conducted a comparative study in the largest pediatric cohort to date including 191 cases and 97 samples from adult patients and analyzed the mutational landscape. We detected overlapping molecular profiles but also significant differences in the mutational pattern. Samples from pediatric patients show a higher frequency of mutations in ID3, DDX3X and BAF-complex components ARID1A and SMARCA4, while YY1AP1 and BCL2 are more frequently mutated in cases from adult BL patients. Correlation of the mutational profile with clinical data was available for the pediatric cohort and identified TP53 mutations to be highly significantly associated with the incidence of relapse thus identifying the first molecular marker to be associated with the incidence of relapse in pediatric BL. As the hotspot analysis of TP53 mutations showed mostly gain of function mutations, it is tempting to speculate that drugs decreasing the amount of malignant TP53 or increase the abundance of wildtype TP53 could be a promising approach for future treatment regimens to further improve prognosis.

  Study EGAS00001005270

• Duplexseq_of_the_interstrand_crosslinks_WGS

  One of the most dangerous forms of DNA damage are interstrand crosslinks (ICLs), which covalently crosslink the two strands of the DNA double helix. The repair of these lesions is crucial for cellular survival due to their ability to block transcription and DNA replication. Initially, the major pathway that has been described in ICL repair involves a network of 22 genes that are mutated in a severe human genetic disease known as Fanconi Anemia (FA). Using synthetic lethality screens in the near-haploid human HAP1 cell line, we recently identified two potentially novel regulators of ICL repair, C1orf112 and THAP12. Loss of C1orf112 and THAP12 causes hypersensitivity to ICL-inducing DNA damaging agents, such as Mitomycin C (MMC). Additionally, C1orf112-depleted cells show elevated levels of micronuclei and accumulation of DNA damage in S-phase. To better understand how C1orf112 and THAP12 mediate the repair of ICLs, we want to perform mutational signature analysis, using the BotSeq method. Therefore, WT, C1orf112 and THAP12 knockout cells were cultured in vehicle or MMC treated conditions for 10 days and the genomic DNA was isolated. FANCA and FANCD2 knockout cells are taken along as controls in this experimental setting.

  Study EGAS00001006545

• Foundation Medicine Genomic Data Used to Identify Prognostic Markers and Fusion Genes in Multiple Myeloma

  The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance. In addition, chromosomal rearrangements that result in oncogenic kinase activation are present in many solid and hematological malignancies, but none have been reported in multiple myeloma (MM). Here we detected fusion genes in 1.5% of patients. These fusion genes were in-frame and the majority of them contained kinase domains from either receptor tyrosine kinases (ALK, ROS1, NTRK3, and FGFR1) or cytoplasmic kinases (BRAF, MAP3K14, and MAPK14) which would result in the activation of MEK/ERK, NF-κB or inflammatory signaling pathways. Fusion genes were present in smoldering MM, newly diagnosed MM and relapse patient samples indicating they are not solely late events. Most fusion genes were subclonal in nature, but one EML4-ALK fusion was clonal indicating it is a driver of disease pathogenesis. Samples with fusions of receptor tyrosine kinases were not found in conjunction with clonal Ras/Raf mutations indicating a parallel mechanism of MEK/ERK pathway activation. Fusion genes involving MAP3K14 (NIK), which regulates the NF-κB pathway, were detected as were t(14;17) rearrangements involving NIK in 2% of MM samples. Activation of kinases in myeloma through rearrangements presents an opportunity to use treatments existing in other cancers.

  Study EGAS00001002874

• scRNA-seq of a 3D human cortical tissue model from human iPSCs exploring 2D versus 3D co-culturing

  Single-cell RNA-seq analysis of human iPSC-derived microglia/astrocytes/neurons in a novel, human in vitro 3D cortical tissue model, as well as 2D co-cultures for comparison. Samples include distinct conditions as described in the Study section. The dataset was generated using the BD Rhapsody technology and sequenced paired-end with Illumina NovaSeq2000. Information on the multiplexing of samples is reported in the Analyses section.

  Dataset EGAD50000002021

• The impact of the human leukaemia virus HTLV-1 on host gene expression

  PBMCs were purified from blood samples of 8 HTLV-1 infected individuals, and cryo-preserved in fetal calf serum containing 10% DMSO. DNA from each samples was extracted using Qiagen Blood & Tissue kit according to the manufacturer's protocol. 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 please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001004169

• Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

  Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

  Study EGAS00001004063

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006642

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006643

• Identification of the dismal subtype of B-ALL with dysregulation of CDX2 and UBTF

  PURPOSE: Advance in the knowledge of genomic basis of B-cell acute lymphoblastic leukemia (B-ALL) has changed the treatment approaches and diagnostic assays and improved their outcome. Despite the recent development of next generation sequencing approaches, there are still some cases that their drivers are unknown. We aimed to define and describe the characteristics of an additional B-ALL subtype by integrating genomic, transcriptomic, and epigenomic approach. METHODS: More than 2,000 B-ALL cases of RNA-seq data from from Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) (n=764), the Children's Oncology Group (COG), Munich Leukemia Laboratory (MLL) (n=280), and other several collaborators were analyzed to identify the new subtype. Whole genome sequence was performed to detect mutations, stractural variants, and copy number alterations. The tridimentional analysis of chromatin was performed with HiChIP. RESULTS: We identified the new high-risk B-ALL subtype “CDX2/UBTF” that exhibited unique gene expression profiles, which is enriched in female (77.3%), adolescents and young adults (52.6%), and relapse cohort (3.3%). CD10 negativity and IgM positivity are hallmarks of this subtype with NTRK3 expression that can be an effective marker at diagnostic approach and a potential targeted therapy with TRK and mulkinase inbitors, larotrectinib and entrectinib. Genetically, two different alterations define CDX2/UBTF. One is UBTF-ATXN7L3 fusions caused by deletion of 17q21.31, and the other is extopic CDX2 expression through the enhancer hijacking mechanism induced by deletion of 13q12.2. Other genomic features include gain of 1q and PAX5 rearrangement (PAX5-ZCCHC7), might induce upregulation of histone cluster genes and PAX5. CONCLUSION: We described the novel B-ALL subtype “CDX2/UBTF” that has unique clinical and genomic characteristics.

  Study EGAS00001005863

• RNA-seq of Ewing sarcoma tumors (ICGC)

  Ewing sarcoma (ES) is a primary bone tumor initiated by an EWSR1-ETS gene fusion. To characterize the transcriptome of Ewing sarcoma, RNA-seq was performed.

  Study EGAS00001003333

• Complex-I stratification of Parkinson's disease in the prefrontal cortex - bulk RNA seq

  Dataset corresponding to the bulk RNA seq dataset from prefrontal cortex for a total of N=98 samples. Tissue samples correspond to patients with idiopathic Parkison's disease (PD) with varying levels of Complex-I activity (N=79) and neurologically healthy controls (N=19). RNA seq was carried out using ribosomal depletion. A subset of these samples was additionally sequenced using single nucleus RNA seq and is available in the same Study as an additional Dataset.

  Dataset EGAD50000000433

• 16S rRNA gene V4 region sequencing data, ASV profiles, and sample metadata of human faecal samples predominantly from the Estonian population

  This dataset comprises 16S rRNA gene V4 region amplicon sequencing data generated from 1,826 human faecal samples, predominantly from the Estonian population. The dataset includes raw sequencing reads and processed amplicon sequence variant (ASV) outputs, consisting of ASV abundance tables, representative ASV sequences, and taxonomic assignments. In addition, a sample metadata table is provided, containing sample and host information, including sample identifier, sequencing run identifier, date of sampling, sex, age, height, weight, nationality, disease status, and Bristol stool type. Sequencing was performed using the Illumina MiSeq and iSeq 100 platforms. The cohort includes individuals with no reported disease (n = 889), gastrointestinal diseases (n = 217), allergies and asthma (n = 194), thyroid gland disorders (n = 117), cardiovascular diseases (n = 103), various general health conditions (n = 139), cancer (n = 28), diabetes (n = 20), gynaecological issues (n = 7). Disease status was unavailable for 112 samples.

  Dataset EGAD50000002306

• Acral Melanoma PDXs from the admixed Brazilian Population - Tumour and unfiltered PDX sample CRAM files - RNAseq

  Patient Derived Xenograft RNAseq sample CRAM files mapped to build GRCh38. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

  Dataset EGAD00001015742

• Efficacy of two different FGFR-inhibitors in a patient with extrahepatic cholangiocarcinoma harboring an FGFR2 mutation

  Cholangiocarcinomas (CCAs) is a type of cancer with few effective systemic therapies. Elucidation of the molecular landscape of the disease from genomic studies based on next generation sequencing (NGS) has contributed to the introduction of new targeted therapies. One of these treatments consists of a class of small molecules that target members of the FGFR family of receptor tyrosine kinases. These drugs are effective and have been approved for cholangiocarcinomas with fusions or rearrangements of FGFR genes. In contrast, the role of these inhibitors in cholangiocarcinomas with mutations in FGFR genes is less well defined. We report here a patient with a cholangiocarcinoma bearing a FGFR2 p.Ser252Trp mutation. The patient was treated with two different FGFR inhibitors, as the first caused ocular toxicity. She obtained clinical benefit from both. This case illustrates the efficacy of FGFR inhibitors on cholangiocarcinoma with specific point mutations. This is the first case to report the clinical benefit of these drugs in FGFR2 p.Ser252Trp mutation. Clinical benefit can be sustained, as seen in our patient. Our case also shows that FGFR inhibitors-induced adverse effects, such as ocular toxicities, may not recur after re-challenge with an alternative drug of the same class.

  Study EGAS50000000015

• Botswana 15 autosomal unlinked microsatellites

  Population structure was investigated in 990 Botswana individuals according to ethno-linguistics, Bantu and Khoisan, and geography (the nine administrative districts) using the AmpFLSTR Identifiler autosomal microsatellite markers. Genetic diversity and forensic parameters were calculated for the overall population, and according to ethno-linguistics and geography. The overall combined power of exclusion (CPE) was 0.9999965412 and the combined match probability 6,28 x 10-19. CPE was highest for the Khoisan Tuu ethnolinguistic group and the Northeast District at 0.9999582029 and 0.9999922652 respectively. CMP ranged from 6.28 x 10-19 (Khoisan Tuu) to 1,02 x 10-18 (Northwest district). Using pairwise genetic distances (FST), analysis of molecular variance (AMOVA), factorial correspondence analysis (FCA), and the unsupervised Bayesian clustering method found in STRUCTURE and landscape genetics software TESS, ethno-linguistics were found to have a greater influence on population structure than geography. FCA showed clustering between Bantu and Khoisan, and within the Bantu. This Bantu sub-structuring was not seen with STRUCTURE and TESS, which detected clustering only between Bantu and Khoisan. The patterns of population structure revealed highlight the need for regional reference databases that include ethno-linguistic and geographic location information. These markers have important potential for bio-anthropological studies as well as for forensic applications.

  Study EGAS00001002380

• Metabolic Biomarkers in Thoracic Cancers

  Here we present RNA sequencing (RNA-Seq) of non-small cell lung cancer (NSCLC) and adjacent lung tissue. These samples were acquired from primarily untreated, surgically resected primary tumors. The first analysis published with this data was to determine the metabolic signatures between primary tumors and adjacent lung tissue.The associated clinical trial (NCT02095808) includes patients with many kinds of thoracic cancers, including NSCLC and other diseases, such as thymoma and esophageal adenocarcinoma. However, the current dbGaP data is focused on the NSCLCs described in the associated paper.

  Study phs003880

• High-depth whole genome sequencing of paired ductal carcinoma in-situ (DCIS) and germline control samples from 51 individuals.

  Deposited here are whole-genome sequencing data for 51 paired breast cancer DCIS and matched-normal samples taken from the same individual. Average sequence depth is 110x for DCIS samples and 39x for matched-normals. Matched-normals are from blood (n=14) or adjacent normal breast (n=37). Sequencing was performed on Illumina HIseqX (n=70) or Illumina Novoseq (n=32). They are a part of a broader project that uses high-depth WGS to investigate the somatic mutation genomic landscape of DCIS in order to uncover biological insights into breast cancer progression as well as possible methods to stratify DCIS patients for individualised therapy or disease monitoring.

  Dataset EGAD50000002071

• Carbamazepine-induced hypersensitivity reactions in Europeans

  An antiepileptic drug carbamazepine is well tolerated by the majority of patients, but can cause severe and potentialy fatal hypersensitivity reactions in a small number of individuals. The aim of this study was to identify genetic predictors of hypersensitivity reactions to carbamazepine. We undertook a genome-wide association study (GWAS) in 22 patients of European ancestry with carbamazepine-induced hypersensitivity syndrome (HSS) and compared our data with genotypes from a healthy population within the WTCCC. We performed imputation of classical HLA alleles according to a recently described method (Science. 2010 Dec 10;330(6010):1551-7. Epub 2010 Nov 4). GWAS statistical analysis was performed using logistic regression with an additive model of inheritance.

  Study EGAS00000000037

• Single cell sequencing of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

  The quantity of tumor infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival particularly in triple negative and HER2-overexpressing BC subtypes. Whilst T cells are the predominant TIL population, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6311 T cells isolated from human BCs, and show for the first time that significant heterogeneity exists in the infiltrating T cell population. We demonstrated that high TIL BCs contained significant numbers of CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple negative breast cancer (TNBC) and provided better prognostication compared with CD8 expression alone. Our data suggests that CD8+ TRM contribute to BC immunosurveillance and are the key targets of modulation through immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.

  Study EGAS00001002845

• Copy numbers in resectable gastric cancer treated with surgery alone

  Purpose: Gastric cancer is a heterogeneous disease requiring stratification to recognize its underlying biology and variable clinical outcome. The Cancer Genome Atlas (TCGA) recognizes four molecular subgroups: Epstein-Barr virus positive (EBV+) and microsatellite instable (MSI) with superior survival compared to genomically stable (GS) and chromosomal instable (CIN). Since classification criteria to distinguish GS from CIN were not defined, alternative markers such as Lauren’s histopathology or CDH1/p53 immunohistochemistry are commonly applied. Here we compared survival of gastric cancer subgroups determined by four methods. Experimental Design: EBV- and microsatellite stable tumors from a total of 309 patients treated with surgery alone were assigned to subgroups by: (i) specific copy number aberrations as determined by TCGA (GS or CIN), (ii) genome instability index (GII; high or low), (iii) Lauren’s classification (diffuse or intestinal), and (iv) CDH1/p53 immunohistochemistry (IHC; aberrant CDH1, normal-, or aberrant p53 expression). Subgroups were associated with cancer-related survival (CRS). Results: Five-year CRS was 42.0% for diffuse and 49.5% for intestinal type tumors, and 57.8% for GS and 41.6% for CIN tumors. Classification by GII or CDH1/p53 IHC did not correlate with CRS. The combination of TCGA and Lauren classifications resulted in four distinct subgroups. Five-year CRS for GS-intestinal (n=24), GS-diffuse (n=57), CIN-intestinal (n=142) and CIN-diffuse (n=86) was 61.4%, 56.5%, 47.6%, and 31.5%, respectively. Conclusions: TCGA’s GS and CIN have additional prognostic value to Lauren’s diffuse and intestinal subgroups in gastric cancer. GS-intestinal, GS-diffuse, CIN-intestinal and CIN-diffuse constitute biologically distinct entities and are suggested as stratification variables for future studies.

  Study EGAS00001007394

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Emory Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study contains variant calls derived from the whole genome sequence data of an early-onset coronary artery disease case-control cohort selected from Emory University Cardiovascular Biobank. Case status was assigned based on the presence of myocardial infarction, coronary artery stenosis greater than 70% in at least one coronary artery, and/or revascularization (coronary angioplasty with or without stent placement or coronary artery bypass grafting) at an early age. For these samples "early age" is defined as men 60 years of age or younger and women 70 years of age or younger. The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases.

  Study phs001880

• TenK10K Phase 1: Whole Genome Sequencing SNP + indels multi-sample VCFs

  SNP and indel variants were called for 1,925 samples from phase 1 of the TenK10K project. Variant calling from WGS alignments to the GRCh38 reference assembly was performed using GATK4 HaplotypeCaller in DRAGEN mode. These VCFs consist of common (>=1% minor allele frequency [MAF]) and rare (<1% MAF) variants . This dataset is comprised of autosomal variants provided as multisample compressed VCF format files. Principal component scores were derived by using gnomAD’s run_pca_with_relateds method.

  Dataset EGAD50000002377

• Analysis of a cohort of familial ademomatous polyposis patients bearing APC gene mutation

  large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the Adenomatous polyposis coli (APC) gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. APC is therefore considered a tumor suppressor gene. While the role of APC in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. We investigated an array of immune cell features in FAP subjects carrying APC mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. In particular, the expression of 579 immune response genes was analyzed in whole blood cells using the Nanostring nCounter Human Immunology kit v2. (Cuche C. et al. Frontiers in Immunology, 2023, in press)

  Study EGAS00001007237

• Immunophenotyping in a COVID-19 Cohort (IMPACC) Transcriptomics and Genotyping Assays

  IMPACC (IMmunoPhenotyping Assessment in a COVID-19 Cohort) is a prospective longitudinal cohort study (NCT04378777) launched in May 2020 in response to the worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institute of Health (NIH). Patient enrollment and sample analysis involved 20 hospitals associated with 15 U.S. biomedical research centers and 11 centralized Core immunoassay laboratories.The study aimed to enable the identification of potential biomarkers and inform future therapeutic interventions using a longitudinal approach encompassing the whole disease course for a comprehensive understanding of the contributions of the pathogen and host immune response in modulating the manifestations, severity, and post-acute sequelae of the infection. IMPACC enrolled close to 1200 adult symptomatic, molecularly confirmed hospitalized COVID-19 patients in the study within 48 hours of their hospital admission. Clinical data and biological samples (blood, mid-turbinate nasal swabs, and esophageal aspirant) were collected according to minimal risk guidelines at enrollment and on days 4, 7, 14, 21, and 28. Biological samples were collected at 3-month intervals up to 12 months after hospital discharge to assess functional and immunologic recovery measures. Sample collection, processing, and storage procedures were standardized across sites, and samples were transported to centralized assay-specific core laboratories (Core Labs) in batches for testing and analysis. The description of outcome severity was not limited to survival versus death but encompassed a clinical trajectory approach using 5 groups leveraging longitudinal data based on time in the hospital, disease severity by ordinal scale based on the degree of respiratory illness, and presence or absence of limitations at discharge. Disease severity was assessed based on the degree of respiratory illness using a 7-point ordinal scale adapted from the World Health Organization COVID-19 and NIAID disease ordinal severity scales. DNA for genetic analyses was collected from whole blood at a single time point. To identify any genomic determinants of severe COVID-19 disease, single-nucleotide polymorphism (SNP) genotyping and exome sequencing were conducted to assess genetic variants associated with individual susceptibility to severe disease. In addition, IMPACC included bulk transcriptomic analysis of upper airway (nasal swaps) samples, lower airway (esophageal aspirant) samples, and peripheral blood mononuclear cells (PBMCs) to evaluate dynamic changes in cellular composition and cellular response during the course of the disease. Reads were aligned to the GRCh38 human reference genome. Additional information for the IMPACC study has been submitted to The Immunology Database and Analysis Portal (ImmPort) under study accession SDY1760. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Dr. Steven Kleinstein (steven.kleinstein@yale.edu).

  Study phs002686

• Genetic Basis of Hepatosplenic T Cell Lymphoma (HSTL)

  Hepatosplenic T cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown.  Through whole exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy number alterations in the disease. Chromatin modifying genes including SETD2, INO80 and ARID1B were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates novel gene mutations linked to HSTL pathogenesis and potential treatment targets.

  Study EGAS00001002182

• Transcriptome of CD4+ T cells and CD8+ T cells in glioblastoma multiforme

  Patients included in this study were over 18 years of age and had a histology-confirmed diagnosis of glioblastoma multiforme (GBM). Exclusion criteria were the previous administration of any anti-tumor therapy including radiation therapy. All patients gave written informed consent. The study was approved by the local ethics committee (TUM Medical school) and conducted following the Declaration of Helsinki. During resection of the tumors, tumor tissue and tissue from normal appearing brain within the operative channel was collected. Blood was drawn during the surgical procedure. Single cell suspensions were prepared from the tumor tissue, the normal appearing brain, and the blood. CD4+ T cells and CD8+ T cells were sorted by flow cytometry. Only patients with a complete set of specimens (CD4+ tumor infiltrating lymphocytes (TIL), CD8+ TIL, CD4+ T cells from normal appearing brain, CD8+ T cells from normal appearing brain, blood-derived CD4+ and CD8+ T cells) containing a minimum of 1000 cells in each sorted sample were further analyzed (n=9). Total RNA was isolated from sorted cell populations using the RNAeasy Plus micro kit (Qiagen, 74034). Quality and integrity of total RNA was controlled on a Bioanalyzer 2100 (Agilent Technologies). Library preparation for bulk-sequencing of poly(A)-RNA was done as described previously (Parekh et al., 2016). Briefly, barcoded cDNA of each sample was generated with a Maxima RT polymerase (ThermoFisher Scientific, EP0742) using oligo-dT primer containing barcodes, unique molecular identifiers (UMIs) and an adaptor. Ends of the cDNAs were extended by a template switch oligo (TSO) and full-length cDNA was amplified with primers binding to the TSO-site and the adaptor. NEB UltraII FS kit was used to fragment cDNA. After end repair and A-tailing, a TruSeq adapter was ligated and 3'-end-fragments were finally amplified using primers with Illumina P5 and P7 overhangs. In comparison to previous descriptions (Parekh et al., 2016), the P5 and P7 sites were exchanged to allow sequencing of the cDNA in read 1 and barcodes and UMIs in read 2 to achieve a better cluster recognition. The library was sequenced on a NextSeq 500 (Illumina) with 59 cycles for the cDNA in read 1 and 16 cycles for the barcodes and UMIs in read 2. Data were processed using the published Drop-seq pipeline (v1.0) to generate sample- and gene-wise UMI tables (Macosko et al., 2015). Reference genome (GRCh38) was used for alignment. Transcript and gene definitions were used according to the Genecode Annotation Version 35.

  Study EGAS50000000156

• scRNAseq and scTCRseq of three tumor lesions derived from one patient receiving adoptive TIL therapy

  scRNA sequencing and scTCR sequencing on three tumor lesions derived from one patient receiving adoptive tumor-infiltrating lymphocyte (TIL) therapy. Expanded metastasis was used for TIL expansion and yielded the TIL product which also was used for scTCR sequencing. 10 weeks after transfer of the TIL product the regressing metastasis was resected. After the patient progressed the progressing metastasis was removed (61 weeks).

  Dataset EGAD50000000406

• Whole genome sequencing of tumor samples from advanced pre-treated NSCLC patients recruited in a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab.

  Acquired or de novo resistance to immune checkpoint inhibitors occurs in the majority of advanced non-small cell lung cancers (NSCLC). There is an unmet need to improve outcomes for patients with this condition. Oncolytic viruses represent an attractive treatment approach due to their dual activity in inducing tumor cell lysis directly and potentially augmenting anti-tumor immunity. Here, we present the safety, efficacy and translational findings from a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab in patients with advanced pre-treated NSCLC. We performed paired biopsies pre- and post-treatment in 10 patients who received intravenous CVA21 and pembrolizumab, 8 of whom had prior treatment with immune checkpoint inhibitor (ICI) therapy. Whole genome sequencing and spatial proteomics were performed to comprehensively characterise the response to CVA21. Combination CVA21/pembrolizumab (anti PD-1) therapy was well tolerated with no serious treatment-related adverse events. Partial responses were seen in two patients with prior acquired anti-PD-1 resistance and disease stabilisation in 6 patients, giving a clinical benefit rate of 80%. High baseline tumor mutational burden and PD-L1 expression were observed in patients with better response to treatment. Interestingly, an increase in antigen presentation and CD8+ T cell infiltration was observed on treatment compared with baseline in patients with better progression-free survival. This study demonstrates the potential of CVA21 to modulate the immunogenicity of tumor cells and remodelling the tumor microenvironment, providing novel insights for patient selection for trials involving novel immunotherapeutic approaches.

  Study EGAS00001008258