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• Detection of cancers three years prior to diagnosis using plasma cell-free DNA

  A major goal of early cancer detection is to identify subclinical disease when the tumor burden is low, so that treatments are more effective. But how early can cancers be detected prior to clinical signs or symptoms? This question can be answered only through the evaluation of participants whose clinical course has not been altered by the study itself. We here describe such an evaluation, performed on prospectively collected plasma samples from the Atherosclerosis Risk in Communities (ARIC) study, including 26 participants diagnosed with cancer and 26 matched controls. At the index time point, eight of these 52 participants scored positively with a multicancer early detection (MCED) blood test. All eight of these participants were diagnosed with cancer within 4 months after blood collection. In six of these 8 participants, we were able to assess an earlier plasma sample collected 3.1 to 3.5 years prior to clinical diagnosis. In four of these six participants, the same mutations detected by the MCED test could be identified, but at 8.6 to 79-fold lower levels. These results demonstrate that it is possible to detect circulating tumor DNA (ctDNA) more than three years prior to clinical diagnosis, and provide benchmark sensitivities required for the success of ctDNA-based tests for this purpose.

  Study EGAS00001008068

• Evaluation of somatic mutations in urine samples as a non-invasive method for the detection and molecular classification of endometrial cancer

  Purpose: Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was to evaluate somatic mutations in urine to accurately discriminate endometrial cancer patients from controls. Experimental Design: Overall, 72 samples were analyzed using next-generation sequencing with molecular identifiers targeting 47 genes. We evaluated urine supernatant samples from women with endometrial cancer (n=19) and age-matched controls (n=20). Cell pellets from urine and plasma samples from seven cases were sequenced; further, we also evaluated paired tumor samples from all cases. Finally, immunohistochemical markers for molecular profiling were evaluated in all tumor samples. Results: Overall, we were able to identify mutations in DNA from urine supernatant samples in 100% of endometrial cancers. In contrast, only one control (5%) showed variants at a variant allele frequency (VAF)≥2% in the urine supernatant samples. The molecular classification obtained by using tumor samples and urine samples showed good agreement. Analyses in paired samples revealed a higher number of mutations and VAFs in urine supernatants than in urine cell pellets and blood samples. Conclusions: Evaluation of somatic mutations using urine samples may offer a user-friendly and reliable tool for endometrial cancer detection and molecular classification. The diagnostic performance for endometrial cancer detection was very high, and cases could be molecularly classified using these noninvasive and self-collected samples. Additional multi-center evaluations using larger sample sizes are needed to validate the results and understand the potential of urine samples for the early detection and prognosis of endometrial cancer.

  Study EGAS00001007396

• CRLF2_sequencing_project_Exomes

  I hope to gain insight into novel genetic aberrations present in these patients that will highlight important pathways that are involved in this subtype of leukaemia. It would be interesting to see if the mutations and pathways that are activated are consistent between the patients, or differences are observed dependent upon whether the patient has the translocation or the PAR1 deletion. Of note is the high association with either numerical gains of chromosome X or numerical/structural abnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. I hope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. By including the three patients that are normal for CRLF2, but have consistent genetic abnormalities found in the experimental cohort, I expect to find genetic differences between these two groups that will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000081

• Somatic mutations in twin breast cancers (2019-04-03)

  The aim of this study is to investigate the somatic mutations in twins with BRCA1/2 negative breast cancer with no strong family history. . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004890

• Prostate Cancer Upgrading Reference Set

  This study aimed to investigate clinical, demographic, and molecular features of men diagnosed with low-risk prostate cancer [ISUP Grade Group 1 (GG1)] at biopsy who underwent radical prostatectomy, and for whom an increased tumor grade (ISUP Grade Group 2 or above) was subsequently detected in the resected prostate. This phenomenon is termed upgrading. In collaboration with the Early Detection Research Network (EDRN), a blinded reference set was established to facilitate upgrading biomarker detection and validation. A prospective, multi-institutional, cohort of men with the GG1 prostate cancer and intention to undergo prostatectomy was recruited. Biospecimens (blood, urine) were collected and this biorepository comprises the official EDRN Upgrading Reference Set (URS). Recording of case-control status (case = upgrading at prostatectomy, control = no upgrading at prostatectomy) was coordinated by the Data Management and Coordinating Center (DMCC) of the EDRN, who ensured blinding of all participating researchers. A subset of the reference set (n = 192) was chosen to undergo whole genome sequencing (WGS) for the investigation of a germline genomic biomarker of upgrading. Variant calls from all sequenced URS whole genomes are available through dbGaP, with the exception of one sample for which sequencing was not successful. Among investigated clinical features, prostate-specific antigen (PSA) density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. Two polygenic risk score-based biomarkers were computed in the genetic sub-cohort and tested against case-control status. Neither was predictive of upgrading.

  Study phs003670

• Tumor-specific expression of let-7i and miR-192 is associated with resistance to cisplatin-based chemoradiotherapy in patients with larynx and hypopharynx cancer

  Background: The majority of patients with locally advanced larynx or hypopharynx squamous cell carcinoma are treated with organ preserving chemoradiotherapy (CRT). Clinical outcome following CRT varies greatly. We hypothesized tumor microRNA (miRNA) expression is predictive for outcome following CRT. Methods: Next-generation sequencing (NGS) miRNA profiling was performed on 37 formalin fixed paraffin embedded (FFPE) tumor samples. Patients with a recurrence free survival (RFS) of less than 2 years (“poor outcome”) and patients without recurrence within 2 years (“good outcome”) were compared by differential expression analysis. Tumor-specific miRNAs were selected based on normal mucosa miRNA expression data from The Cancer Genome Atlas database. A model was constructed to predict outcome using group-regularized penalized logistic ridge regression. Candidate miRNAs were validated in the initial sample set by RT-qPCR as well as in 46 additional tumor samples.Results: 1,938 known mature miRNAs were detected. Thirteen miRNAs were differentially expressed (p<0.05, FDR<0.1) according to outcome group. Initial class prediction in the NGS cohort (n=37) resulted in a model combining five miRNAs and disease stage, able to predict CRT outcome with an area under the curve (AUC) of 0.82. In the RT-qPCR cohort (n=83), 25 patients (30%) experienced early recurrence (median RFS 8 months; median follow-up 42 months). Class prediction resulted in a model combining let-7i-5p and miR-192-5p and disease stage, able to discriminate with an AUC of 0.80 patients with good versus poor clinical outcome.Conclusion: The combined miRNA expression and disease stage prediction model is superior to using either factor alone. ¬¬¬This study indicates NGS miRNA profiling using FFPE specimens is feasible, resulting in clinically relevant biomarkers.

  Study EGAS00001004001

• Utility of ctDNA to support patient selection for early phase clinical trials: The TARGET Study

  Next generation sequencing (NGS) of circulating tumour DNA (ctDNA) supports blood-based genomic profiling but is not routinely implemented in the clinic. TARGET is a molecular profiling programme with the primary aim to match patients to early phase clinical trials based on analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumour and results were turned round within a clinically acceptable timeframe for Molecular Tumour Board (MTB) review. When applying a 2.5% Variant Allele Frequency (VAF) threshold actionable mutations were identified in 41/100 patients, with 11 of these patients going onto a matched therapy. These data support the application of ctDNA in an early phase trial setting where broad genomic profiling of contemporaneous tumour material enhances patient stratification to novel therapies and provides a practical template for bringing blood-based analyses to the clinic.

  Study EGAS00001003407

• Neoadjuvant immune checkpoint blockade in mismatch-repair proficient colon cancers

  Immune checkpoint blockade has led to paradigm shifts in the treatment of various tumour types, yet limited efficacy has been observed in patients with metastatic mismatch-repair proficient (pMMR) colorectal cancer. Here we report an in-depth analysis of patients with early-stage pMMR colon cancer from the phase II NICHE study (ClinicalTrials.gov: NCT03026140). A total of 31 patients received neoadjuvant treatment of nivolumab plus ipilimumab followed by surgery. The response rate was 26% and included six patients with a major pathological response (≤10% residual viable tumour). One patient with an ongoing clinical complete response did not undergo surgery. Responses were observed despite a low tumour mutational burden in all tumours, while chromosomal genomic instability scores were significantly higher in responders compared to non-responders. Responding tumours were more likely to be TP53 mutant, KRASG12 wildtype and had significantly higher baseline expression of proliferation signatures and TCF1. Imaging mass cytometry also revealed a higher percentage of Ki-67+ cancer and Ki-67+ CD8+ T cells in responders compared to non-responders. Meanwhile, in non-responders, we observed an enrichment for an inflamed-fibrotic microenvironment associated with TGF-β expression, hinting towards possible resistance mechanisms. These results provide a comprehensive analysis of response to neoadjuvant ICB in early-stage pMMR colon cancers and identify potential biomarkers for patient selection.

  Study EGAS50000000856

• Organ_maturation_in_preparation_for_birth__Peds_RFA__to_develop_a_tissue__resource_and_a_single_cell_atlas_of_organ_development_and_maturation_for__dissemination_among_the_scientific_and_clinical_community__RNA

  Knowledge about abnormal organ development is important to understand pathology and to develop novel treatment approaches for individuals with congenital and acquired disease. Most of our current understanding is based on examination of tissues from the embryo and early foetus, collected from women undergoing termination of pregnancy in the first trimester (third) of pregnancy. There is very little known about normal and abnormal organ development from a developmental perspective during the crucial last two-thirds of pregnancy when much remodelling of foetal tissues occurs. This study will generate a single-cell atlas of late-foetal lungs, blood, heart, bone and immune organs.

  Study EGAS00001008256

• Single-cell and bulk RNA-sequencing of nivolumab-treated glioblastoma

  Glioblastoma is a highly aggressive type of brain tumour for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected glioblastoma patients, and it is currently not well understood what separates the few responders from the non-responders at the cellular and molecular level. Here we investigate the phenotypic and transcriptional evolutionary dynamics at single-cell resolution during nivolumab immune checkpoint treatment of eight glioblastoma patients enrolled in a translational phase I/II clinical trial.

  Study EGAS00001007110

• Acetalax and bisacodyl triple-negative breast cancer RNA-Seq

  Analysis of gene expression in triple negative breast cancer xenografts exhibiting good or bad response upon acetalax and bisacodyl treament.

  Study EGAS50000000618

• Whole exome sequencing of 184 unrelated subjects with 22q11.2 deletion syndrome (DiGeorge syndrome/velo-cardio-facial syndrome)

  Our goal is to find genetic modifiers of major phenotypes in patients with 22q11.2 deletion syndrome, also known as DiGeorge syndrome or velo-cardio-facial syndrome. Whole exome sequencing was performed as part of a contract to the NHLBI, Resequencing and Genotyping Service. We have obtained cardiac phenotype information from the de-identified subjects enrolled in the study, either by echocardiography report or medical doctor report. All of the subjects have a 3 million base pair 22q11.2 deletion flanked by low copy repeats, LCR22, A-D.

  Study phs000987

• GDAP___Genome_Diversity_in_Africa_Project

  The Genomic Diversity in Africa Project (GDAP) started with the plan to develop a genomic resource from African populations, characterise genomic diversity and population history, and facilitate clinical studies in Africa. Currently, 25 individuals from 24 ethnolinguistic groups have been whole-genome sequenced at high depth totalling 585 individuals. An additional 41 individuals have been sequenced with 10X Genomics libraries. At this stage, the initial curation of this dataset has been finished and we are performing the analysis in coordination with our collaborators. The current state of the GDAP represents a very diverse panel of African populations that maximizes geographical and ethnic variation and represents a great starting point to achieve the aforementioned goals. However, southern sub-Saharan countries, Bantu speakers and hunter gatherer groups are currently underrepresented, despite being crucial to understand the evolutionary history of the continent. After extensive effort to collate studies documentation, we finally have the opportunity to sequence 600 new individuals from these groups, including countries as Gabon, Rwanda and Zambia, and address these deficiencies. We aim to proceed with the same strategy: to sequence at high depth 25 individuals with standard PCR free libraries, with 2 additional individuals with 10X Genomics Chromium libraries per ethnolinguistic group. The former allows a good representation of variants down to low frequency in any given population, and the latter allows accurate phasing and the analysis of structural variation. By including these new populations, we want to investigate three crucial questions in African history in addition to the initial objectives: the Bantu expansion, the evolutionary history of hunter gatherers and the transatlantic slave trade. Additionally, the expanded dataset will help us better discover the genetic variation present in Africa and characterize the African pangenome. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003602

• Whole-Exome Sequencing analyses in tamoxifen-associated endometrial cancer

  An increased incidence of endometrial cancer has been described for patients that have received tamoxifen to treat breast cancer. Using samples from endometrial tumors, isolated from surgivcal specimens of patients who previously received tamoxifen treatment for breast cancer, we aimed to identify whether there are specific somatic mutations enriched in this population, relative to endometrial tumors from the general population. For this, WES was performed on matched endometrial tumors and healthy tissue (n=21).

  Study EGAS00001006453

• ATAC-seq

  ATAC-seq data for 26 CLL samples (7 controls, 19 tumor) of the CancerEpiSys-PRECiSe project.

  Dataset EGAD00001005967

• MutWP1: CRUK Grand Challenge Mutographs of Cancer: kidney (2019-03-26)

  This dataset contains all the data available for this study on 2019-03-26.

  Dataset EGAD00001004867

• The Innate Immune Response as a Therapeutic Target for Cutaneous Leishmaniasis

  The overall goal of the proposed project is to identify innate host functions that contribute to cure or failure during antileishmanial drug therapy, and their related biomarkers. Results from this project enabled the identification of host-specific predictive and prognostic signatures of therapeutic responsiveness, and the bases for rational selection of host-targeted therapeutics that redirect inflammation and revert pathogenicity. Through sequential transcriptomic profiling of blood monocytes (Mo), neutrophils (Nφ), and eosinophils (Eφ) over the course of systemic treatment with meglumine antimoniate, we discovered that a heightened and sustained Type I interferon (IFN) response signature is a hallmark of treatment failure (TF) in Cutaneous Leishmaniasis (CL) patients. The transcriptomes of pre-treatment, mid-treatment and end-of-treatment samples were interrogated to identify predictive and prognostic biomarkers of TF. Results from this study instigate the evaluation of Type-I IFN responses as new immunological targets for host-directed therapies for treatment of CL, and highlight the feasibility of using transcriptional signatures as predictive biomarkers of outcome for therapeutic decision making.

  Study phs003545

• Biomarkers in Transplant Recipients

  Biliary atresia causes jaundice and liver failure in newborn children. In this study, single nucleotide polymorphisms were characterized in children with biliary atresia and identified ARF6 as a susceptibility gene for this disease. Knockdown of this gene in zebrafish embryos impaired formation of bile ducts and excretion of bile from the zebrafish liver. Subject enrollment: Children with biliary atresia were enrolled at Children's Hospital of Pittsburgh (CHP) after obtaining written consent from parents for the University of Pittsburgh IRB approved protocol number 0405628. At the Center for Applied Genomics (CAG), all subjects were enrolled after obtaining written consent from parents per Children's Hospital of Philadelphia IRB approval number 06-004886 Genotyping array: Genotyping of DNA obtained from blood was performed with the Infinium HumanHap550K BeadChip (Illumina, San Diego, CA). Statistical methods and software: SNP genotype frequencies were compared between cases and controls with a chi-square test statistic applied in Plink [Purcell et al, 2007] for SNPs with at least 90% call rate and 1% minor allele frequency (MAF). Cases and controls: All DNA samples had excellent data quality with call rates > 98%. A total of 63 Caucasian BA cases and 1907 controls were compared at > 550000 SNPs, and demonstrated a very low genomic inflation factor of 1.00627. Description of Cases: Biliary atresia patients had received a Kasai procedure and demonstrated histopathological features of biliary obstruction, and were recruited at evaluation for transplantation or after liver transplantation.

  Study phs000960

• Microbiomic and immunogenic biomarkers of adjuvant chemotherapy efficacy in stage III colorectal cancer

  The standard treatment for stage III colorectal cancer (CRC) is surgery, followed by adjuvant chemotherapy (AC). However, the efficacy of AC is limited, and approximately 30% of patients experience recurrence. Therefore, easily assessable molecular biomarkers that can predict response to AC are needed. Here, we aimed to identify predictive biomarkers of response to AC using tumor transcriptomic data. Tumor specimens from 253 patients who underwent surgery for stage III CRC between 1997 and 2019 were analyzed using RNA sequencing. Transcriptional subtyping and analyses of gut microbiome, immune cell fractions, and T-cell receptor (TCR) were performed to identify factors associated with recurrence-free survival (RFS) in patients treated with or without AC. Of 253 patients, 118 (46.6%) received AC. Twenty phyla and 799 species of the microbiomes were identified, among which Fusobacteria were identified in 247 patients (97.6%). Multivariable Cox proportional hazards regression analysis of patients who received AC showed that intratumoral Fusobacterium and M1 macrophage abundance and diversity of TCR alpha and delta (TRAD) were independently associated with RFS. Fusobacterium and M1 macrophage abundance, and TRAD diversity were associated with the response to AC, suggesting that these factors could serve as biomarkers for personalized treatment in stage III CRC.

  Study JGAS000875

• Treatment of genetic screening of hypertriglyceridemia type I, III, and V - HTG Amsterdam

  This is a cohort of patients with extreme hypertriglyceridemia. Patients have been screened for loss of function mutations in LPL, GPIHBP1, APOC2, APOA5 and LMF1.

  Study phs000511

• Longitudinal Studies of Brain Structure and Function in MPS Disorders

  Mucopolysaccharidosis (MPS) types I, II, IV, VI and VII, are inherited diseases that result from the bodies inability to break down large sugar molecules that are by-products of metabolism. MPS affects most organs of the body and causes abnormalities in the liver, spleen, bones, and brain. We are studying the central nervous system (primarily the brain) so we can better understand the nature of the problems individuals with MPS I, II, IV, VI and VII have so we can find ways of better treating these problems. We would like to find out about the changes in the brain of individuals with MPS I, II, IV, VI and VII using data from MRI and neuropsychological tests. This is a longitudinal study so patients who enroll will need to be seen 3 times over 5 years. The longitudinal nature of the study allows us to make conclusions about how changes in some structures of the brain and changes in cognitive ability are related. The research objectives are: To identify abnormalities of brain (and central nervous system) structure and function in patients with MPS I, II, IV, VI and VII, regardless of how they are being treated or have been treated in the past; and to track disease progression over time. To examine the degree to which independent variables (e.g., age at first treatment, severity of disease, types of medical abnormalities, mutation, medical events, and sensory abnormalities) have an impact on both functional and structural outcomes as well as on quality-of-life. To identify, through longitudinal study, those measures that most accurately reflect the current disease state. This is a longitudinal study of 75-100 individuals with either MPS I, II, IV, VI and VII. Those participating in the study will be evaluated 3 times over 5 years. The primary site for this study is the University of Minnesota but there are an additional 6 centers in the United States and Canada that are also participating and will provide data for analysis. You will need to be able to travel to Minnesota or one of the participating centers in order to be a part of this study.

  Study phs001328

• Somatic_Variation_Angiosarcoma

  Through whole genome sequencing, this study will explore the mutational profiles and signatures within an angiosarcoma tumour from a patient with xeroderma pimentosum. Very little information is known about this tumour type and it has not previously been studied within the context of xerogerma pigmentosum.

  Study EGAS00001002610

• The chemotherapeutic CX-5461 is extremely mutagenic and may increase cancer risk

  The chemotherapeutic agent CX-5461 or pidnarulex has been fast-tracked by the US FDA for treatment of BRCA1-, BRCA2-, and PALB2-mutated cancers. It is under investigation in Phase I/II clinical trials. Here we find that although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, non-selective, collateral mutagenesis in all cells, to magnitudes that exceed known environmental carcinogens, raising public health concerns regarding its potential for promoting secondary cancers.

  Study EGAS50000000023

• Sequencing_probands_and_families_with_severe_insulin_resistance_syndromes

  This is an ongoing project and continuation to all the sequencing we have been doing over the last few years. We have some additional families and probands with syndromes of insulin resistance not previously sequenced within uk10k or other core funded projects. We would like to complete the sequencing in all of the good quality families and probands we have, this would require another ~50 samples to be WES sequenced. This cohort has already proven to be a rich source of interesting findings with papers in Science and Nature genetics.

  Study EGAS00001000488

• Dedifferentiated Melanoma (2021-02-02)

  De- and transdifferentiation of melanoma is a rare histopathological phenomenon that has not be characterised genetically. In this project we plan to sequence the genomes of de and transdifferentiated cases so as to define their genetic make-up. . This dataset contains all the data available for this study on 2021-02-02.

  Dataset EGAD00001006931