12300 results for "cancer rna-seq"

in 54.54 milliseconds.

• Comprehensive Genomic Profiling of a National Cohort of Pediatric Papillary Thyroid Carcinoma in Hungary

  Pediatric papillary thyroid carcinoma (PTC) is a rare childhood malignancy with increasing incidence and distinct clinicopathological features, including high rate of locoregional metastases and different molecular background compared to adult cases. Traditional treatments (surgery, radioactive iodine) are effective but pose long-term risks, prompting the exploration of targeted therapies. We performed comprehensive genomic profiling on 21 pediatric PTC patients utilising the Illumina TruSight Oncology 500 platform and detected mutations, gene fusions, copy number variations and revealed tumor mutational burden.

  Study EGAS50000001833

• Catalogue Statistics

  EGA Statistics Bibliography Growth Community Archive Distribution Catalogue What is in the EGA? The European Genome-phenome Archive (EGA) overview The EGA archives and distributes the results of several types of studies. Such studies include genome-wide association studies (GWAS), different purpose sequencing and molecular diagnosis assays among others. Moreover, these studies target many different kind of diseases from cancer to neurodegenerative alterations. We summarised all this data in the charts below. The statistics are computed daily based on an updated list of studies. Each pie chart depicts a different aspect of the studies: which disease type was studied, which type of sampling method was used and what was the scope of the genomic analysis. Number of studies per disease type Studies in the EGA by disease barHorizontalChart('disease-graph', 'https://stats.ega-archive.org/catalog/by_disease') Number of studies per technology type Studies in the EGA by technology barHorizontalChart('technology-graph', '/stats/studies/technology', 'Include dbGaP') Number of studies per sample type Studies in the EGA by samples barChart('samples-graph', '/stats/studies/sample-types', 'Include dbGaP')

  Documentation about/statistics/catalogue

• RNAseq___Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000813

• Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000812

• Amplicon_based_sequencing_of_drug_resistant_organoids

  A BRAF V600E colorectal organoid which is sensitive to MAP kinase inhibition was mutagenised with the chemical mutagen ENU and then drug selected using a combination of Trametinib, Dabrafenib and Cetuximab. Single cell derived organoids were then manually picked and expanded in drug. Resistance was confirmed in a 14 day assay and DNA was collected. These then underwent targeted amplicon-based sequencing to confirm candidate resistance effectors from a screen in 2 2D BRAF V600E colorectal cell lines. Pools of resistant clones were also sequenced.

  Study EGAS00001001639

• ENU_LS_411N_TripleTherapy

  BRAF V600E colorectal cancers do not respond to the only currently FDA approved targeted therapy for CRC. There is currently a trial underway in the UK recruiting V600E CRC patients for treatment with a triple therapy combination of Cetuximab, Trametinib and Dabrafenib. We have mutagenized a pool of V600E CRC cell lines and treated with this triple therapy to select out drug resistant clones. We will now sequence these drug resistant clones with the aim of identifying common point mutations engendering resistance to this new therapy.

  Study EGAS00001001777

• Mutational_burden_in_human_hair_follicles

  We would like to dissect human hair follicles and assess the mutations found in diffferent parts of the follicle eg bulge, root etc. We can also compare this with mutations found in the surrounding epidermis of the same patients (this is done under a different study). This may provide insights into the origin of PTCH1 mutants frequently seen in basal cell carcinoma but so far not located in our whole epidermis work as well as defining the clonality of the hair follicle

  Study EGAS00001004462

• Genome and transcriptome sequence data from a metastatic cholangiocarcinoma patient

  Genome and transcriptome sequence data from a metastatic cholangiocarcinoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002976

• Genome and transcriptome sequence data from a rectal adenocarcinoma patient

  Genome and transcriptome sequence data from a rectal adenocarcinoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002973

• Genome and transcriptome sequence data from a cholangiocarcinoma patient

  Genome and transcriptome sequence data from a cholangiocarcinoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002991

• Genome and transcriptome sequence data from a leiomyosarcoma patient

  Genome and transcriptome sequence data from a leiomyosarcoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002996

• Constit Genome Sequencing

  WGS blood data (fastq raw read sequences) for French ICGC leiomyosarcoma cancer sequencing project, 67 samples representing 67 donors. Sequencing was performed on Illumina HiSeq. The libraries were then sequenced with a 2 x 100bp paired-end protocol to a minimum mean coverage of 30x.

  Dataset EGAD00001003190

• Whole exome and targeted DNA sequencing data for formalin-fixed paraffin embedded tissue from de novo small cell prostatic carcinoma cases

  This dataset consists of 44 compressed paired fastq files, 15 of which are generated from whole exome sequencing, and 29 of which are generated from DNA sequencing using a targeted gene panel capturing the exonic regions of 73 prostate cancer driver genes. Targeted DNA sequencing was performed on an Illumina MiSeq (v3 600 cycle kit), and exome sequencing was done using an Illumina HiSeq 2500 (v4 250 cycle kit) machine. The fastq files are named in accordance with the sample aliases provided, which reflect the pathology of interest to this study (small cell prostatic carcinoma--SCPC), whether it was sequenced using an exome or targeted gene panel, whether the FFPE sample was sourced from tumor or benign tissue (labeled T or B, respectively), and whether there exists multiple samples belonging to a single patient.

  Dataset EGAD00001004139

• The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer (CIN3+)

  We analysed DNA methylation at >850,000 CpG sites across the genome using the Illumina EPIC array in a total of 1,254 cervical liquid-based cytology samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). We developed the WID-CIN-test which is a DNA methylation signature consisting of 5,000 CpG sites.

  Study EGAS00001005078

• Transcriptomic predictors of survival for palbociclib + endocrine therapy vs. capecitabine in aromatase inhibitor-resistant breast cancer from GEICAM/2013-02 PEARL

  We examined transcriptomic tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET vs. capecitabine in aromatase inhibitor-resistant HR+/HER2- MBC. PAM50 intrinsic subtype predicted PFS differences between palbociclib + ET and capecitabine, and lower B-cell-associated gene expression predicted longer OS with palbociclib + ET vs. capecitabine. These features may help identify HR+/HER2- tumors resistant to further ET-based treatment with CDK4/6 inhibitors.

  Study EGAS00001008177

• SPECTA: NGS Screening Program for Efficient Clinical Trial Access

  SPECTA comprises a network of participating European clinical sites and NGS screening platforms that can screen individual patients for multiple molecular targets and potentially allow the design of trials that will match the specific biology of the diseases affecting specific patients with cancer.

  Dataset EGAD00001000894

• Guardians of the genome: protecting DNA from endogenous sources of damage

  Mutational signatures are imprints of cell-intrinsic and extrinsic pathophysiological processes that have occurred through tumorigenesis. Experimental efforts to explore signature etiologies have produced a compendium of signatures of exogenous mutagens previously. Here, we unearth major sources of endogenous DNA damage and the genes that are critical to mitigating this innate stream of DNA damage under normal, physiological circumstances. We performed whole genome sequencing of 173 subclones of CRISPR-Cas9 knockouts of 43 genes in a human induced pluripotent stem cell system, in the absence of any added DNA damage. We reveal substitution and indel signatures that arise from those genes which are essential guardians of the genome. By detailed dissection and comparisons to cancer-derived signatures, we demonstrate interminable sources of constitutive DNA damage, and some mechanistic knowledge into how guardian genes preserve the genome. Based on these experimental insights, we develop and benchmark a tool for clinical classification of tumor samples.

  Dataset EGAD00001006055

• Prediction of HLA genotypes using NGS data

  High-precision human leukocyte antigen (HLA) genotyping is crucial for anti-cancer immunotherapy, but existing tools predicting HLA genotypes using next-generation sequencing (NGS) data are insufficiently accurate. We compared the availability and accuracy of eight HLA genotyping tools (OptiType, HLA-HD, PHLAT, seq2HLA, arcasHLA, HLAscan, HLA*LA, and Kourami) using 1,275 cases from the 1000 Genomes Project data and created a new HLA-genotyping algorithm combining tools. Then, we assessed the new algorithm’s performance in 39 in-house samples with normal whole-exome sequencing (WES) data and polymerase chain reaction–sequencing-based typing (PCR-SBT) results.

  Dataset EGAD00001007733

• Spatial transcriptome sequence data from cross section of cancer containing prostates

  Spatial transcriptome sequence data from two tumour containing prostates. Entire cross section of organ divided into cubes to fit spatial transcriptomics arrays. The dataset contains paired-end sequences from 21 sections of 1k array sections and 9 sections of 10x Visium sections for patient 1 as well as 28 sections of 10x Visium sections for patient 2.

  Dataset EGAD00001008644

• Dataset for bone_cancer-WHOLE_GENOME

  Rare cancer sequencing data of 48 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008866

• Dataset for breast_cancer-EXON

  Rare cancer sequencing data of 94 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008868

• Dataset for cancer_of_unknown_primary-EXON

  Rare cancer sequencing data of 62 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008870

• Dataset for colorectal_cancer-EXON

  Rare cancer sequencing data of 119 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008871

• Dataset for GIST-EXON

  Rare cancer sequencing data of 64 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008875

• Dataset for GIST-WHOLE_GENOME

  Rare cancer sequencing data of 18 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008876

• Dataset for gynecologic_cancer-WHOLE_GENOME

  Rare cancer sequencing data of 38 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008878

• Dataset for head_and_neck_cancer-WHOLE_GENOME

  Rare cancer sequencing data of 56 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008879

• Dataset for liposarcoma-WHOLE_GENOME

  Rare cancer sequencing data of 48 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008888

• Dataset for melanoma-WHOLE_GENOME

  Rare cancer sequencing data of 22 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008889

• Dataset for melanoma-EXON

  Rare cancer sequencing data of 76 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008890

• Dataset for NSCLC-WHOLE_GENOME

  Rare cancer sequencing data of 34 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008894

• Normal sample for patient SA238

  Whole genome sequencing of normal sample for triple negative breast cancer patient SA238

  Dataset EGAD00001009363

• Normal sample for patient SA221

  Whole genome sequencing of normal sample for triple negative breast cancer patient SA221

  Dataset EGAD00001009362

• Tumour sample for patient SA280

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA280

  Dataset EGAD00001009361

• Tumour sample for patient SA291

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA291

  Dataset EGAD00001009360

• Tumour sample for patient SA289

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA289

  Dataset EGAD00001009359

• Tumour sample for patient SA286

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA286

  Dataset EGAD00001009358

• Tumour sample for patient SA495

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA495

  Dataset EGAD00001009357

• Tumour sample for patient SA425

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA425

  Dataset EGAD00001009356

• Tumour sample for patient SA423

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA423

  Dataset EGAD00001009355

• Tumour sample for patient SA300

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA300

  Dataset EGAD00001009354

• Tumour sample for patient SA239

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA239

  Dataset EGAD00001009353

• Tumour sample for patient SA238

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA238

  Dataset EGAD00001009352

• Tumour sample for patient SA221

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA221

  Dataset EGAD00001009351

• Tumour sample for patient SA683

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA683

  Dataset EGAD00001009350

• Tumour sample for patient SA682

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA682

  Dataset EGAD00001009349

• Tumour sample for patient SA681

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA681

  Dataset EGAD00001009348

• Tumour sample for patient SA680

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA680

  Dataset EGAD00001009347

• Tumour sample for patient SA679

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA679

  Dataset EGAD00001009346

• Tumour sample for patient SA678

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA678

  Dataset EGAD00001009345

• Tumour sample for patient SA677

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA677

  Dataset EGAD00001009344

• Tumour sample for patient SA676

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA676

  Dataset EGAD00001009343

• Tumour sample for patient SA675

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA675

  Dataset EGAD00001009342

• Tumour sample for patient SA674

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA674

  Dataset EGAD00001009341

• Tumour sample for patient SA673

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA673

  Dataset EGAD00001009340

• Tumour sample for patient SA218

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA218

  Dataset EGAD00001009177

• Tumour sample for patient SA219

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA219

  Dataset EGAD00001009178

• Tumour sample for patient SA272

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA272

  Dataset EGAD00001009179

• Tumour sample for patient SA274

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA274

  Dataset EGAD00001009180

• Tumour sample for patient SA275

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA275

  Dataset EGAD00001009181

• Tumour sample for patient SA276

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA276

  Dataset EGAD00001009182

• Tumour sample for patient SA279

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA279

  Dataset EGAD00001009183

• Tumour sample for patient SA283

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA283

  Dataset EGAD00001009184

• Tumour sample for patient SA287

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA287

  Dataset EGAD00001009185

• Tumour sample for patient SA394

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA394

  Dataset EGAD00001009186

• Tumour sample for patient SA395

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA395

  Dataset EGAD00001009187

• Tumour sample for patient SA398

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA398

  Dataset EGAD00001009188

• Tumour sample for patient SA402

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA402

  Dataset EGAD00001009189

• Tumour sample for patient SA404

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA404

  Dataset EGAD00001009190

• Tumour sample for patient SA530

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA530

  Dataset EGAD00001009191

• Tumour sample for patient SA585

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA585

  Dataset EGAD00001009192

• Tumour sample for patient SA586

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA586

  Dataset EGAD00001009193

• Tumour sample for patient SA588

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA588

  Dataset EGAD00001009194

• Tumour sample for patient SA591

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA591

  Dataset EGAD00001009197

• Tumour sample for patient SA592

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA592

  Dataset EGAD00001009198

• Tumour sample for patient SA593

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA593

  Dataset EGAD00001009199

• Tumour sample for patient SA590

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA590

  Dataset EGAD00001009196

• Tumour sample for patient SA589

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA589

  Dataset EGAD00001009195

• Tumour sample for patient SA595

  Whole genome sequencing of tumour sample for triple negative breast cancer patient SA595

  Dataset EGAD00001009200

• Ither2 WXS dataset - Implementation of pediatric precision oncology into clinical practice: The individualized Therapies for Children with cancer program “iTHER”

  iTHER is a prospective national precision oncology program aiming to define tumor molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory pediatric tumors in order to identify relevant aberrations to inform treatment.

  Dataset EGAD00001010178

• Whole genome sequencing data of high-grade serous ovarian cancer samples (set 6)

  Whole genome sequencing data of 31 high-grade serous carcinoma (HGSC) patients (101 samples) sequenced with HiSeq X Ten and BGISEQ-500

  Dataset EGAD00001010202

• Organoid Derivation Project - GRCh38 - WGS (2023-06-22)

  Sequencing of tissue samples and their derived organoids from oesophageal, pancreatic and colorectal cancer patients. . This dataset contains all the data available for this study on 2023-06-22.

  Dataset EGAD00001011093

• Genome and transcriptome sequence data from a metastatic carcinoma of unknown primary patient

  Genome and transcriptome sequence data from a metastatic carcinoma of unknown primary patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001011020

• The Genomic Landscape of Mongolian Hepatocellular Carcinoma

  Background and Hypotheses: Mongolia has the highest reported incidence of - and mortality from - hepatocellular carcinoma (HCC) in the world, which is between three and seven times higher than that observed in other high-incidence populations, such as South Korea, Thailand, and China. Although its causative factors and underlying tumor biology remain unknown, risk factors such as chronic hepatitis B virus and/or hepatitis C virus infection are highly prevalent. Moreover, Mongolia has an extraordinarily high prevalence of hepatitis delta virus (HDV), more than ten times above the global estimate, which we hypothesize as a major driver of Mongolian hepatocarcinogenesis. By performing a comprehensive and integrative genomic characterization, we aimed to identify robust molecular subclasses and driver features informative of the etiology and progression of the disease. This study, the first one of this nature ever to be conducted on a Mongolian cohort, identifies similarities to previous studies performed on other populations (which reflect general characteristics of liver carcinogenesis) as well as unique features of Mongolian HCC. Study Design and Methods: Clinical information and paired tumor/non-tumor liver tissue samples were obtained from 76 HCC patients undergoing surgery at the National Cancer Center of Mongolia. Transcriptome sequencing and whole exome sequencing were performed on all tumor and non-tumor samples, followed by bioinformatics processing and quality control. Consensus clustering and regularized Cox regression analyses were performed on transcriptome data. Driver mutations and mutational signatures were assessed. These results were compared to those from 373 HCC patients of different races and ethnicities and diverse etiologies. Furthermore, molecular subclass gene signatures from multiple previous studies were assessed for validation. Results and Conclusions: Using a transcriptomics-based unsupervised approach, we identified four molecular subclasses among Mongolian HCC cases, which were associated with different patient survival outcomes. These molecular subclasses were mapped to signatures reported in other HCC cohorts, showing significant associations consistent with survival outcomes. A supervised analysis determined risk scores strongly associated with survival, consistent with the four molecular subclasses. Mutational signature analysis using recently published COSMIC and Environmental Agents Compendia identified signatures with distinct prevalence among HDV+ and HVD- groups. Signatures differentially associated with HDV+ include mutational patterns linked to alkylating agents (such as temozolomide), tobacco chewing and exposures to 1,8-Dinitropyrene and furan, whereas HDV- appeared differentially associated with aristolochic acid II. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits several unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which may be linked to HDV infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.

  Study phs002000

• Germ Cell and Associated Heme Malignancies Evolve from a Common Shared Precursor

  Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15-40. While most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal non-seminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggests a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals has not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of fifteen patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced TP53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor which gives rise to the parallel evolution of GCTs and blood cancers in these patients. Reprinted from PMID: 32897884, with permission from JCI.

  Study phs002231

• The Spatio-Temporal Evolution of Multiple Myeloma from Baseline to Relapse-Refractory States

  In multiple myeloma, the spatio-temporal evolution patterns of cancer cells in the bone marrow remain largely unknown. Here, we applied spatial-longitudinal sequencing, including a total of 179 samples collected from 25 patients during a follow-up of up to 14 years. Our study highlights focal bone lesions (FL) as hotspots of tumor evolution and provides possible explanations for their negative prognostic impact. We show a close phylogenetic relationship between baseline FL and relapse clones. In patients with ≥3 FDG-PET-positive FL at diagnosis, relapse was driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion was typically seen (p<0.01). Applying imaging-guided sampling, we identified a novel evolutionary pattern with unique treatment-resistant sub-clones at distinct locations. We observed multiple selective clonal sweeps, resistant clones that can be hidden over years, and epigenetic modifier mutations as a new class of relapse aberrations. Here we show that imaging can enhance tumor evolution studies and response assessment. The sophisticated evolution mechanisms in myeloma and presence of single cells that can drive relapse even after 10 years of remission suggest that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.

  Study phs002625

• GATA2 Deficiency

  The aim of this study is to identify somatic mutations that contribute to the progression of GATA2 Deficiency patients from bone marrow failure to myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML). We investigated somatic mutations in >100 patients by whole exome and myeloid malignancy targeted array sequencing to identify acquired mutations associated with myeloid malignancies. MDS was the most common diagnosis (~45%), followed by GATA2 Bone Marrow Immunodeficiency Disorder (G2BMID) (~35%). Approximately ten percent of our cohort were unaffected "carrier" family members with no disease manifestations. In contrast, about ten percent had progressed to a proliferative leukemia. There were no correlations with GATA2 mutation, patient age or gender and disease progression or survival. Somatic Recurrent somatic mutations were uncommon in cancer associated genes, and virtually absent in asymptomatic patients. However, mutations in the cohesin gene STAG2 and chromatin remodeling gene ASXL1 were detected in ~20% of patients. Patients with ASXL1 mutations had a lower survival. ASXL1 mutations were ~10-times more prevalent in female patients than males. Other recurrent mutations were in the DNMT3A, BCOR, and SETBP1 genes. There was a conspicuous absence of the most commonly mutated genes associated with myeloid malignancies, including TET2, RUNX, IDH1/2 and splicing factor genes. 

  Study phs002311

• Integrated Genomic Analysis of Periampullary Tumors at The Human Genome Sequencing Center, Baylor College of Medicine (HGSC-BCM)

  Adenocarcinomas arising in the complex environment of the ampulla of Vater constitute a histopathological heterogenous group, presumably originating from the different epithelial cellular constituents present at the site: pancreas, bile duct, and intestinal duodenum. These tumors have been described in many different ways: intra-ampullary, periampullary, intra-ampullary papillary-tubular neoplasm, ampullary-ductal, periampullary-duodenal, and ampullary-not otherwise specified. These varied classifications reflect the difficulty in classifying these tumors into specific groups. Only the tumors clearly localized in the bile duct or duodenum are identified as distal cholangiocarcinomas (CAC) or duodenal adenocarcinomas (DUOAC). The current classification is based on macroscopic features that may distinguish the epithelium of origin, microscopic features, clinicopathological criteria, histopathology and expression of differential markers. This classification is subjective and prone to inter-observer variability and significantly impacts on treatment selection and therapeutic development. In order to define subtypes of periampullary cancer with clinical relevance, we performed whole exome sequencing and copy number analysis of 160 cancers arising in the periampullary region, 62 of these clearly arising from either the bile duct (n = 44), or the duodenum (n = 18) and 98 periampullary cancers (AMPAC) where the epithelium of origin could not be clearly defined.

  Study phs000895

• Tandem DNA Repeats Activate hTERT Gene Transcription

  Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell and chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of E-boxes, cooperated with the proximal promoter in hTERT regulation by bHLH transcription factors and maintained hTERT expression during embryonic stem cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations.  To assess the genetic polymorphism of VNTR2-1 in human populations, we analyzed genomic DNA samples of Caucasian Americans and African Americans enrolled in the Georgia Centenarian Study.  VNTR2-1 in these genomic DNA samples were PCR amplified and subjected to sequencing analysis usinb the PacBio® SMRT method. The result showed that all VNTR2-1 alleles in Caucasian Americans contained 76 or more 42-bp repeats, whereas 32% of VNTR2-1 alleles in African Americans had fewer than 76 repeats.  

  Study phs002428

• Pre-Existing Skin-Resident CD8 and γδ T Cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy

  Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immunotherapy. Here, we attempted to identify novel predictive biomarkers of response through extensive and deep multi-omics interrogation of 186 samples from 116 patients. We collectively integrated bulk RNAseq, single-cell RNAseq, multiplex immunofluorescence, and spatial transcriptomics. Importantly, we were also able to study 14 matched pairs of tissue samples from pre- and post-immunotherapy. In non-responders, tumors show evidence of increased tumor cell cycling, expression of neuronal stem cell markers, and IL-1α/β. Responders have evidence of increased type I/II interferon signatures and evidence of pre-existing tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of multiple T cell receptors. Spatial transcriptomics demonstrated higher co-localization of T cells with B and dendritic cells in responders, with evidence of expression of chemokines important for co-stimulation. Finally, immunotherapy increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors in responders, further underscoring their therapeutic importance. These data identify potential novel actionable biomarkers and therapeutic targets for MCC.

  Study phs003629

• Finding the way towards the eradication of therapy-related myeloid neoplasms

  Therapy-related neoplasms are directly caused by the drugs used to eradicate a previous cancer. It is well known that a subset of drugs designed to kill cancer cells through DNA-damage-induced apoptosis can intrinsically, as secondary effect, cause DNA-damage in other cells, thus inducing a neoplasm. Those neoplasms have especially bad prognosis. Why are these drugs still in use? Because for many diseases we do not have anything better, at the moment. Approximately 0.5-1% of the kids treated for various types of cancers develop a therapy-related myeloid neoplasm (tMN) as a result of the treatment. Despite having the same origin, their prognostic and molecular features are different from the adult ones, and a complete understanding of the pathogenesis of tMN in children is still missing. A total of 84 paediatrics neoplasms have been profiled by either Whole Genome or Whole Exome sequencing by Jason R. Schwartz and his colleagues, in a collaborative effort guided at the St. Jude Children's hospital, in Memphis. They identified a mean of 28 somatic mutations per patient, a number which is significantly bigger than the number of mutations found in paediatrics primary neoplasms, as depicted in the original paper's figure 1b, shown here. Their sequencing data identified that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements as the most frequent drivers of the disease. Clonal evolution analysis (the comparative study of the behaviour of cells harbouring different mutations) highlighted that, unlike in adults’ tMN, there were not pre-existing leukemic clones, and virtually all mutated cells were found arising as a direct consequence of cytotoxic therapy. This represents yet another important difference between adult and paediatric tMN. This important study have been published in Nature communications in February 2021. The sequencing data have been deposited at EGA under the study number EGAS00001004850. Thanks to this, other researchers around the world could re-use it to uncover more information, integrate and validate their studies. Revealing the molecular features underlying the development of cancers is the only way towards the development of new generation targeted therapies, which will allow us to finally drop the cytotoxic drugs eliciting such unwanted and catastrophic secondary effects as tMN. It is not an overstatement to say that, while improving the treatment of primary tumours, we could entirely eradicate therapy-related neoplasms right from their origin. Looking forward.

  Blog eradication-of-therapy-related-myeloid-neoplasms

• Exome sequencing identifies mutation of the ribosome in T-cell acute lymphoblastic leukemia

  Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and responds well to therapy in children, but not in adults. We used exome sequencing of 67 T-cell ALL (T- ALL) samples to gain insight in the mutational spectrum and age related differences of these leukemias. We detected protein-altering mutations in 508 genes, with an average of 8.2 mutations in pediatric and 21.0 in adult T-ALL. Based on stringent filtering, we predict 15 of these genes to be drivers, including 7 genes that were not previously implicated in T-ALL. We identify CNOT3 as a new tumor suppressor, as it is mutated in 12.2 % of adult T-ALLs and its knock-down causes de novo tumors in a sensitized drosophila eye tumor model. In addition, we identify mutations in RPL5 and RPL10, proteins of the 60S ribosomal complex2, in 18.2 % of pediatric T-ALLs. Mutation of arginine 98 in the X-linked RPL10 gene was most frequent. Yeast cells expressing the Rpl10 R98S mutant showed a clear ribosome biogenesis defect, excluding that this mutation is a passenger mutation. Our data provide insights in the mutational landscape of pediatric and adult T-ALL and identify the ribosome as a potential oncogenic factor in cancer.

  Study EGAS00001000296

• Single-cell profiling reveals mechanisms of response to anti-PD-L1 versus anti-PD-L1 combined with anti-CTLA4 in head and neck squamous cell carcinoma

  Cancer patients often receive a combination of PD-(L)1 and CTLA4 inhibitors, but the mechanisms underlying their concerted actions remain unclear. We conducted a neoadjuvant study in head and neck squamous cell carcinoma (HNSCC) involving anti-PD-L1 monotherapy versus anti-PD-L1/anti-CTLA4 combination. Single-cell profiling of on- versus pre-treatment biopsies confirmed T-cell expansion as response biomarker. We identified a type 1 immune response accompanying T-cell expansion on-treatment across treatment arms, and herein characterized co-localized IgG plasma cell expansion as important contributor. In pre-treatment biopsies, similar features correlated with expansion upon anti-PD-L1, but not anti-PD-L1/anti-CTLA4. By profiling tumor-draining lymph nodes, we found the addition of anti-CTLA4 to trigger activation and subsequent trafficking of CD4+ T-cells via the blood, to become T-helper 1 cells in the tumor. anti-PD-L1/anti-CTLA4 indeed facilitated co-localized expansion of CD4+ and CD8+ T-cells in tumors versus mostly CD8+ T-cells with anti-PD-L1 alone. Hence, we identify complimentary mechanisms underlying anti-PD-L1/anti-CTLA4 therapy in HNSCC.

  Study EGAS50000000037

• Allele Balance Bias Identifies Systematic Genotyping Errors and False Disease Associations

  In recent years, Next Generation Sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many clinical applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing rare diseases need to be identified. Although random sequencing errors can be modeled statistically and deep sequencing minimizes their impact, systematic errors remain a problem even at high depth of coverage. Understanding their source is crucial to increase precision of clinical NGS applications. In this work, we studied the relation between recurrent biases in allele balance (AB), systematic errors and false positive variant calls across a large cohort of human samples analyzed by whole exome sequencing (WES). We have modeled the allele balance distribution for biallelic genotypes in 987 WES samples in order to identify positions recurrently deviating significantly from the expectation, a phenomenon we termed allele balance bias (ABB). Furthermore, we have developed a genotype callability score based on ABB for all positions of the human exome, which detects false positive variant calls that passed state-of-the-art filters. Finally, we demonstrate the use of ABB for detection of false associations proposed by rare variant association studies (RVAS).

  Study EGAS00001003027

• ERG ALTERATIONS DEFINE A NOVEL SUBTYPE OF ACUTE LYMPHOBLASTIC LEUKEMIA

  Structural chromosomal alterations are a hallmark of acute lymphoblastic leukemia (ALL) yet many patients lack an identifiable abnormality on conventional cytogenetic analysis. Here, using integrated analysis of genome-wide DNA copy number and gene expression data of 1764 childhood and adult ALL cases, including whole-genome, exome and mRNA-sequencing of 72 cases, we report a novel subtype of B-progenitor ALL (B-ALL) representing 4-13% of B-ALL cases characterized by a distinct gene expression profile, and focal deletions of ERG (ETS related gene) in 56% of cases. These cases are characterized by expression of a ERG transcript that utilizes a novel exon in intron 6 of ERG spliced to the canonical reading frame of ERG exons 7-10, encoding a 27 kDa C-terminal ERG protein that retains the ETS and transactivating domains but lacks the N-terminal pointed and regulatory domains. This protein is a competitive inhibitor of wild-type ERG and is leukemogenic in vivo. ERG-altered ALL cases have a favourable outcome despite the presence of alterations associated with poor prognosis in non-ERG ALL, such as deletions of IKZF1. These findings identify a new subtype of leukemia characterized by a novel mechanism of ETS transcription factor dysregulation in cancer.

  Study EGAS00001000514

• Inhibiton of the GABPB1L-containing GABP tetramer is sufficient to reverse replicative immortality in TERT promoter mutant glioblastoma cells.

  Over 50 types of cancer acquire TERT promoter mutations. These single point mutations reactivate telomerase, allowing for indefinite maintenance of telomere length and enabling cellular immortalization. The transcription factor binding site created by the point mutations specifically recruit the ETS factor GABP, a multimeric transcription factor composed of the GABPα and GABPβ subunits. GABP can form two functionally independent transcription factor species – a dimer or a tetramer – depending on which of the structurally distinct GABPβ isoforms is incorporated into the complex. In this study, we show that genetic disruption of GABPβ1L, a tetramer forming isoform of GABPβ that is dispensable in normal development, results in TERT silencing in a TERT promoter mutation dependent manner. Failure to activate TERT expression by GABPβ1L culminates in telomere dysfunction, DNA damage, and mitotic cell death exclusively in TERT promoter mutant cells. Furthermore, exogenous expression of TERT is sufficient to prevent telomere degradation and loss of cell viability in GABPβ1L-reduced lines bearing the mutant TERT promoter. Orthotopic injection of tetramer-deficient mutant TERT promoter GBM cells rendered lower tumor burden and prolonged the overall survival of the tumor-bearing mice. These results highlight the potentially widespread role of GABPB1L in enabling replicative immortality of TERT promoter cancers.

  Study EGAS00001002582

• Comparison of structural variations from 10X Genomics linked-reads and conventional Illumina short-reads sequencing

  Structural variations (SVs) are large genomic rearrangements that can drive many diseases. Conventional short-reads whole genome sequencing (cWGS) allows their identification with base-pair resolution, but suffers from high false discovery rate. cWGS taps in short-range information from short-reads while linked-reads sequencing (10XWGS) utilizes long-range information. 10XWGS allows linkage of short-reads originating from the same large DNA molecule with a unique barcode captured in a gel bead in emulsion. This mitigates alignment-based artefacts from cWGS especially in repetitive regions. However, the false discovery rate of this technology is unclear. In this study, we performed a comprehensive analysis of different type and size of SVs predicted from these two technologies. The SVs common between both technologies were found to be highly specific by PCR and Sanger sequencing while validation rate dropped for uncommon events. Further, we propose a novel enrichment approach for filtering out false positive calls from both the technologies independently. To this end, we trained a machine learning model for respective technologies and used it to characterise SVs from MCF7 cell line and a primary breast cancer tumor with high precision. This approach would be valuable in understanding true mechanisms driven by SVs in various diseases.

  Study EGAS00001004093

• Whole exome sequencing on primary retinoblastoma tissues and matching lymphocyte DNA.

  Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control.

  Study EGAS00001001690

• Host whole genome variations are associated with neurocognitive outcome in survivors of pediatric medulloblastoma

  Host whole genome analysis is a promising source of predictive information for long-term morbidity in cancer survivors. However, studies on genetic predictors of long-term outcome, particularly neurocognitive function following chemoradiation in pediatric oncology are limited. In the present study, we evaluated variations in host whole genome single nucleotide polymorphisms (SNPs) and their association with cognitive outcome. Whole-genome SNP analysis of host peripheral blood was conducted on 22 medulloblastoma long-term survivors, of whom 18 completed neuropsychological testing. First, unsupervised consensus clustering of the most variable SNPs within 409 genes involved in DNA repair was performed. Discrete variant groups were identified, although they were not associated with cognitive outcome, suggesting that variations in genes corresponding to a single functional group may be insufficient to predict long-term outcome alone. In support of this interpretation, unsupervised hierarchical clustering analysis using disease-associated gene variants by cognitive impairment status yielded two distinct variant clusters comprised of 36 variants, 34 of which were in noncoding regions. These findings illustrate for the first time that cognitively impaired survivors have a distinct variant profile compared to other medulloblastoma survivors. Future research in larger cohorts is needed to validate host genome predictors of cognitive impairment that may impact clinical management.

  Study EGAS00001002996

• The UVA-induced single-base mutational signature of CX5461 in human cells

  Drug-related UVA-induced photoreactions have been reported for several therapeutic compounds, including fluoroquinolones. CX5461 is a clinically relevant quinolone-derived anti-cancer small molecule with documented UVA-sensitising activity. Here we compared, by bulk and clonal whole genome sequencing (WGS) under light-protected conditions, the mutational signatures in human retinal pigment epithelial cells (RPE1) exposed to UVA, CX5461, or co-exposed to UVA and CX5461. Treatment with CX5461 or UVA alone resulted in a low SNV burden and background-like mutational profiles. In contrast, bulk sequencing of human cells co-exposed to UVA and CX5461 had a markedly higher SNV burden characterized by T>A and T>C substitutions. Furthermore, single-cell clonal expansion and sequencing of CX5461 alone, UVA alone or CX5461+UVA treatments confirmed that the pattern was only observed when cells were exposed to both UVA and CX5461. The CX5461+UVA-associated SNV signature we report arises only when CX5461-treated cells are exposed to UVA, and is not observed when CX5461-treated cells are shielded from light. We do not observe strong single base mutagenic activity of CX5461 alone, under light protected conditions. Our data emphasise the need for appropriate controls and light-exposure precautions when studying base mutagenesis activity of known photosensitiser molecules.

  Study EGAS50000001145