11754 results for "cancer rna-seq"

in 60.97 milliseconds.

• Cancer Genomics of the Kidney

  The aim of CAGEKID is to carry out comprehensive detection of DNA markers for conventional (clear cell) renal carcinoma. The project includes complete analysis of somatic and constitutional DNA variation, methylation patterns and expression in a large number of constitutional/tumor pairs. CAGEKID is a part of the International Cancer Genome Consortium, ICGC.

  Dataset EGAD00001004018

• Whole exome profiling of spatial biopsies of high grade serous epithelial ovarian cancer patients

  This data set is comprised of data from seven distinct high grade serous epithelial ovarian cancer (HGS-EOC) partients, from whom multiple biopsies were taken at the time of surgery, from the ovary and from different locations in the peritoneal cavity. This data set contains 28 samples, sequenced with a whole exome sequencing approach.

  Dataset EGAD00001004154

• Illumina TSO500 DNA Dataset for Manuscript titled: Evaluation of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) Samples from Advanced Non-Small Cell Lung Cancer for Whole Genome, Whole Exome and Comprehensive Panel Sequencing

  Illumina TSO500 DNA Dataset for Manuscript titled: Evaluation of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) Samples from Advanced Non-Small Cell Lung Cancer for Whole Genome, Whole Exome and Comprehensive Panel Sequencing

  Dataset EGAD00001015396

• Carolina Breast Cancer Study (CBCS)

  The Carolina Breast Cancer Study (CBCS), phase III, is a population-based study aiming to understand the social and molecular correlates of breast cancer outcomes, particularly among Black and young women. CBCS recruited first primary breast cancer cases from 44 North Carolina counties between 2008-2013. All cases were between age 20 and 74 and self-identified as female. Black women and young women were systematically oversampled by randomized recruitment such that the study includes approximately 50% Black women and approximately 50% women diagnosed before age 50. A total of 2,998 participants were enrolled. In the ten years following diagnosis, women completed surveys approximately every 1-2 years and diagnoses of subsequent distant local recurrence and second primary tumors were ascertained via linked medical records. We identified records of women who developed secondary breast tumors (including second primary tumors, contralateral breast cancers, and locoregional recurrences), and these participants were oversampled for targeted DNA sequencing using the UNCseq panel (~1200 genes).CBCS germline pathogenic mutations cannot be investigated because participants were consented between 2008 and 2013 with specific language prohibiting this. However, germline data can be used to call somatic mutations or to standardize somatic genomic data.For sharing of study data not included here, please visit unclineberger.org for instructions on submitting a data use agreement.

  Study phs003725

• CancerLocator: Non-Invasive Cancer Diagnosis and Tissue-of-Origin Prediction Using Methylation Profiles of Cell-Free DNA

  Background: The detection and characterization of cell-free DNA in plasma is one of the most promising new areas in cancer diagnosis. Liquid biopsy, unlike traditional tissue biopsy, has the potential to diagnose a variety of different malignancies. Results: Here we propose a probabilistic method, CancerLocator, which exploits the diagnostic potential of cell-free DNA by determining not only the presence but also the location of tumors. CancerLocator simultaneously infers the proportions and the tissue-of-origin of tumor-derived cell-free DNA in a blood sample using genome-wide DNA methylation data. We comprehensively evaluate CancerLocator with simulations and real data, and compare its performance with that of two established multi-class classification methods. We show that the predicted tumor burdens are highly consistent with the true values. In addition, when the proportion of tumor-derived DNAs in the cell-free DNAs is low, the two popular machine learning methods completely fail for cancer diagnosis, while CancerLocator successfully overcomes the challenge. CancerLocator also achieves promising results on patient plasma samples, despite the fact that the DNA methylation data from these samples has very low sequencing coverage. Conclusions: CfDNA methylation may be developed as an important approach for non-invasive early cancer diagnosis.

  Study EGAS00001002211

• CancerDetector: Ultrasensitive and Non-Invasive Cancer Detection at the Resolution of Individual Reads using Cell-free DNA Methylation Sequencing Data

  The detection of tumor-derived cell-free DNA in plasma is one of the most promising directions in cancer diagnosis. The major challenge in such approach is how to identify the tiny amount of tumor DNAs out of total cell-free DNAs in blood. Here we propose an ultrasensitive cancer detection method, termed “CancerDetector”, using the DNA methylation profiles of cell-free DNAs. The key of our method is to probabilistically model the joint methylation patterns of multiple adjacent CpG sites on an individual sequencing read, in order to exploit the pervasive nature of DNA methylation for signal amplification. Therefore, CancerDetector can sensitively identify a trace amount of tumor cfDNAs in plasma, at the level of individual reads. We evaluated CancerDetector on the simulated data, and showed a high concordance of the predicted and true tumor burden. Testing CancerDetector on real plasma data demonstrated its high sensitivity and specificity in detecting tumor DNAs. In addition, the predicted tumor burden showed great consistency with tumor size and survival outcome. Note that all of those testing were performed on sequencing data at low to medium coverage (1X to 10X). Therefore, CancerDetector holds the great potential to detect cancer early and cost-effectively.

  Study EGAS00001002728

• Exome sequencing of a novel cervical cancer cell line

  Human cancer cell lines are largely used in the searching for new antineoplastic agents. However, due to the artifacts of a long-term in culture, cell lines do not always represent the realistic tumor cell behavior. This has motivated the development of models that better mimetics the tumor tissue, among them, the establishment of primary cell cultures. In this work, we establish and characterized a low-passage cervix cancer cell line from a Brazilian patient with squamous cell carcinoma. The phenotype confirms the epithelial and tumor origin, through cytokeratins, EpCAM, and p16 staining. Whole exome sequencing showed relevant somatic mutations in several genes including BRCA2, TGFBR1, and IRX2 genes. CNV analysis by nanostring and WGS revealed amplification in genes related mainly with kinases proteins, involved in proliferation, migration and cell differentiation, such as EGFR, PIK3CA, and MAPK7. Overexpression of EGFR was confirmed by phospho RTK-array and western blot analysis. Furthermore, the cell was sensitivity to cisplatin, with IC50 13 times lower than SiHa cell line. In conclusion, this cervical cancer cell line presents molecular alterations that are an important tool for leading pre-clinical studies of new drugs that target one or more of the altered pathways.

  Study EGAS00001003343

• A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

  Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

  Study EGAS00001002654

• Genomic evolution and transcriptional changes in the evolution of prostate cancer into neuroendocrine and ductal carcinoma types

  Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuro-endocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease and the former often arises on a background of androgen deprivation therapy, although it can al-so arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tis-sue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with 3 longitudinal samples over 5 years. Case 2 was a single time point after development of treatment related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all sam-ples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for the ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small cell neuroendocrine and ductal prostatic carcinoma can have a common an-cestry and the process of evolution over time. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

  Study EGAS00001007412

• Genomic evolution and transcriptional changes in the evolution of prostate cancer into neuroendocrine and ductal carcinoma types (RNAseq)

  Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuro-endocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease and the former often arises on a background of androgen deprivation therapy, although it can al-so arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tis-sue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with 3 longitudinal samples over 5 years. Case 2 was a single time point after development of treatment related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all sam-ples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for the ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small cell neuroendocrine and ductal prostatic carcinoma can have a common an-cestry and the process of evolution over time. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

  Study EGAS00001007428

• Breast cancer bone metastases

  Dac EGAC00001003238

• Cancer Genetics Data Access Commitee

  Dac EGAC00001001742

• Pan Cancer Plasma cfRNA DAC

  Dac EGAC00001003176

• Data Access Commitee FGFR Cancer

  Dac EGAC00001003273

• Breast Cancer Cell Line Data Access Committee

  Dac EGAC00000000015

• Leeds Cancer Genomics

  Dac EGAC00001001156

• SMC Colon cancer team

  Dac EGAC00001001277

• Breast cancer bone metastases

  Dac EGAC00001001548

• PBL Cancer Data Committee

  Dac EGAC00001001870

• bladder cancer data access commitee

  Dac EGAC00001002016

• Cancer Proteomics Mass Spectrometry group

  Dac EGAC00001002236

• OV cancer cell lines DAC

  Dac EGAC00001002307

• Lung cancer cfDNA dataset DAC

  Dac EGAC00001002387

• Lung cancer cfDNA dataset DAC

  Dac EGAC00001002388

• Cancer Team Data Access Committee

  Dac EGAC00001002449

• GIS - NCCS Pancreatic Cancer DAC

  Dac EGAC00001002565

• Lung cancer cfDNA dataset DAC

  Dac EGAC00001002608

• Cancer Team Data Access Committee

  Dac EGAC00001002891

• Pancreatic cancer PDOs/CAFs DAC

  Dac EGAC00001002897

• Pan Cancer Plasma cfRNA DAC

  Dac EGAC00001002956

• DAC for noninvasive lung cancer subtyping

  Dac EGAC00001003474

• Lung cancer cfDNA dataset DAC

  Dac EGAC00001002994

• Ovarian cancer cfDNA dataset DAC

  Dac EGAC00001003234

• Mitochondrial DNA sequencing

  Study EGAS00001005540

• Patient-derived organoids_Vumc

  Study EGAS00001005947

• WGS of PMBCL

  Study EGAS00001006452

• CPTAC: Microscaled Proteogenomic Methods for Precision Oncology

  Cancer proteogenomics combines genomics, transcriptomics and mass spectrometry-based proteomics to gain insights into cancer biology and treatment outcomes. To promote clinical investigation, we developed a "microscaled" proteogenomics approach for tumor-rich frozen core needle biopsies. Tissue-sparing specimen processing ("Biopsy Trifecta EXTraction", BioTExt) and microscaled proteomics (MiProt) generated deep-scale proteogenomics datasets. As a proofof- concept, biopsies were accrued from ERBB2 positive (ERBB2+) breast cancers before and 48 to 72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy. Multi-omics comparisons were conducted between samples associated with residual disease versus complete pathological response (pCR). Integrated analyses diagnosed diverse molecular causes of treatmentresistance including: 1) absence of ERBB2 amplification (false-ERBB2&#43); 2) insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2&#43); 3) resistance features in true-ERBB2+ cases including androgen receptor signaling, mucin expression and an inactive immune microenvironment; 4) lack of acute phospho-ERBB2 down-regulation in nonpCR cases. We conclude microscaled cancer proteogenomics could improve diagnostic precision.

  Study phs001907

• METABRIC: Data from Pereira et al (2016), The somatic mutation profiles of 2433 breast cancers refine their genomic and transcriptomic landscapes. Nat Comms 7.

  The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2433 primary breast tumours that have copy number aberration (CNA), gene expression, and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters, and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intratumour heterogeneity using mutant allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intratumour heterogeneity are in general associated with worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intratumour heterogeneity. These results emphasise the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.

  Study EGAS00001001753

• Analysis of DNA methylation in normal B cells and chronic lymphocytic leukemia

  Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes.As second study using these samples focued on evolution and resulting intra-tumor heterogeneity in CLL. We used 450k bead-chip arrays to study DNA methylomes in 68 chronic lymphocytic leukemia (CLL) cases, including 28 serial cases. The result establishs linked evolution of epigenetic and genetic alterations in progressive disease, revealing an important aspect of the biology of epigenetics in cancer.

  Study EGAS00001000534

• Sequencing of an organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity.

  Kidney tumors are among the most common solid tumors in children, comprising several distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first pediatric cancer organoid biobank. It contains tumor and matching normal organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumors, malignant rhabdoid tumors, renal cell carcinomas, and congenital mesoblastic nephromas. The malignant rhabdoid tumor organoids represent the first organoid model for tumors of non-epithelial origin. The tumor organoids retain key properties of native tumors, useful for revealing patient specific drug vulnerabilities. We further demonstrate that organoid cultures derived from Wilms tumors consist of multiple different cell types, including epithelial, stromal and blastemal-like. Our organoid biobank captures the cellular heterogeneity of pediatric kidney tumors, providing a representative collection of well-characterized models for basic cancer research, drug-screening, and personalized medicine.

  Study EGAS00001003853

• Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

  DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutational consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb) – higher than all childhood and most cancers (>7000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerases epsilon or delta. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germline bMMRD (p<10e-13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase mutant cancers rapidly amass an excess of simultaneous mutations (~600 mutations/cell division), reaching but not exceeding ~20,000 exonic mutations in <6 months. Thus implying a threshold compatible with cancer cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

  Study EGAS00001001112

• MED12L Gene Alterations Define Aggressive BRCA2-Mutant Prostate Cancers

  Germline mutation of BRCA2 increases the lifetime risk of developing prostate cancer (PCa) by over 700%. BRCA2-mutant PCa have poorer prognosis than sporadic PCa, with rapid development of metastatic, castrate-resistant prostate cancer (mCRPC) and 5-year cancer-specific survival rates of ~50-60%1-4. Despite this, unique genomic driver events that explain the aggressiveness of localized BRCA2-mutant PCa are lacking. We used whole-genome sequencing to fully characterize 14 BRCA2-mutant PCa and demonstrate that BRCA2-mutant PCa is associated with increased genetic instability and a mutually exclusive mutational burden when compared to sporadic PCa. Importantly, BRCA2-mutated cancers are defined by unique copy number gains and hypomethylation events, including alterations in the MED12L/MED12 axis, which are found solely in mCRPC and are enriched in PCa tumours harbouring aggressive intraductal carcinoma (IDC-P) pathologic sub-types. Our findings begin to explain the clinical entity of BRCA2-mutated PCa as these tumours have a unique and aggressive genotype de novo, associated with IDC-P and mCRPC, even in the hormone-naive setting.

  Study EGAS00001001615

• Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

  Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which are likely to escape discovery in short reads. We employed Oxford Nanopore Technologies (ONT) sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a complex SV pattern termed "templated insertion thread", characterized by short (mostly less than 1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. Templated insertion threads occur in 3% of cancers, with a prevalence ranging to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in seven cancer-driver genes. Our study shows the potential of long-read sequencing in cancer.

  Study EGAS00001006576

• Broad utility of ultrasensitive analysis of ctDNA dynamics across solid tumors treated with immunotherapy

  Prior studies have suggested the biomarker potential of plasma circulating tumor DNA (ctDNA) in cancer patients treated with immune checkpoint inhibitors (ICIs). In order to characterize the potential role of ultrasensitive ctDNA detection in the management of these patients we have performed tumor whole-genome-informed, ultrasensitive ctDNA analysis—tracking approximately 1,800 tumor-specific mutations per patient—in a retrospective cohort (n=136) and a prospective validation cohort (n=66) across 24 cancer types treated with ICIs alone or in combination with bispecific antibodies or immune cell engagers. Analyzing 1,455 longitudinal samples, we found that ctDNA molecular response measured as early as 3 weeks after treatment initiation correlated with improved progression-free and overall survival, while ctDNA clearance at any time strongly correlated with radiological response and prolonged survival. Additionally, ctDNA dynamics distinguished true progression from pseudoprogression and predicted outcomes in patients receiving continued immunotherapy beyond initial progression. This study highlights the broader applicability of ultrasensitive ctDNA as a biomarker across cancer types and immunotherapy modalities.

  Study EGAS50000001333

• Osteosarcoma_Sequencing

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 25 osetocarcinoma samples and subjected to total of three lanes of 37 bp paired end sequencing on the llumina GA per sample. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000013

• ADCC_Rearrangement_Screen

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 25 adenoid cystic carcinoma samples and subjected to total of eight lanes of 37 bp, paired end sequencing on the llumina GA. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000030

• Cell-Free DNA Genomic Profiling and its Clinical Implementation in Advanced Prostate Cancer

  Sixty-eight patients with advanced prostate cancer in castration-resistant or castration-sensitive settings undergoing treatment at the University Hospital Basel or the St. Claraspital Basel (Switzerland) were selected for targeted parallel sequencing analysis on liquid biopsy (plasma cfDNA) and matched formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples. The liquid biopsy sequencing (plasma cfDNA) was performed using a custom-designed targeted AmpliSeq HD Prostate Cancer cfDNA panel on all 68 patients. The sequencing on 42 matched FFPE tumor biopsy samples was performed using a custom-designed or an alternative commercial panel (ThermoFisher). Raw data underwent automated processing on the Ion Torrent Server v5.16.1 (ThermoFIsher) and were aligned to a hg19 reference genome using the Torrent Alignment Software (ThermoFihser).

  Dataset EGAD50000000348

• Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, including KRAS and ERBB2 (Her2) Driver Mutations

  Neoantigen-specific T cell responses were characterized in 4 patients with non-small cell lung cancer. Candidate neoantigens were identified by sequencing tumor and normal DNA from each patient, and ranking single nucleotide variants by expression. Multiple T cell responses were isolated, and in two patients with lung adenocarcinoma, CD4+ T cell responses to recurrent oncogenic mutations in KRAS and Her2 were identified.

  Study phs001805

• Phase IB/II Study of Bazedoxifene in Combination with Palbociclib in Patients with Endocrine Resistant Hormone Receptor-Positive Breast Cancer

  In this phase Ib/II clinical trial, the investigators evaluated the efficacy and safety of the combination of palbociclib with bazedoxifene in patients with a metastatic endocrine-resistant hormone receptor-positive, HER2-negative breast cancer. Furthermore, whole exome sequencing of cell-free tumor DNA was done on serial samples from these patients, revealing potential molecular changes associated with mechanisms of resistance.

  Study phs002802

• Epigenetic Mechanisms of Inflammation and Fatigue in Head and Neck Cancer

  This was a longitudinal observational study to examine the association between fatigue and DNA methylation as well as gene expression among patients with head and neck cancer. Demographic and clinical variables were collected before chemoradiotherapy and/or at follow-up visits as appropriate. Fatigue was assessed and biosamples (for DNA methylation and gene expression) were collected before, immediately after, and at six- and twelve-months post-chemoradiotherapy.

  Study phs002106

• Brazilian Thyroid WES

  Medullary thyroid cancer (MTC) is a rare malignant tumor that arises from parafollicular cells. Approximately 8% of thyroid cancer cases are MTC, and about 25% of these have a hereditary component. Incorporating molecular parameters into tumor classification is important. Besides, the presence of pathogenic germline variants can impact directly on cancer prevention. Thus, the aim of this study was to perform whole exome sequencing (WES) on a consecutive series of hereditary RET wild-type MTC patients to identify genetic variants that may be involved in the carcinogenesis of this tumor. WES was performed on 28 patients negative for germline RET pathogenic variants using the NovaSeq 6000 platform. Variant classification followed American College of Medical Genetics and Genomics guidelines.Our study represents a significant advancement in gene discovery for MTC genetics.

  Dataset EGAD50000000086

• FOCUS Trial

  We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fl uorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fl uorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset.

  Study EGAS50000000725

• SCANDARE ovarian WES data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 91 frozen samples (n = 53 at baseline, n = 31 Post-NAC, n= 7 Recurrence, and n = 62 germline DNA) from 64 ovarian cancer patients using WES technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001658

• Longitudinal therapy monitoring of ALK-positive non-small cell lung cancer (copy number, cell-free DNA)

  Clinical courses of non-small cell lung cancer patients with ALK rearrangements (ALK+ NSCLC) vary widely. We analyzed 271 longitudinal plasma samples from 73 patients with advanced ALK+ NSCLC treated with ALK tyrosine kinase inhibitors by combined hybrid-capture-based targeted sequencing (average 4,100x coverage) for mutation analysis and shallow whole genome sequencing (0.5x coverage) for global copy number profiling from cfDNA.

  Study EGAS00001004276

• MDSMPN_Rearrangement_Screen

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 11 Myelodysplastic Myeloproliferative neoplasms (MDSMPN) and subjected to total of two lanes of 50 bp, paired end sequencing on the llumina HiSeq. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000034

• Gastric_and_Esophageal_tumour_rearrangement_screen

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from gastric and esophageal tumours and subjected to total of two lanes of 50 bp, paired end sequencing on the llumina HiSeq. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000037

• Splenic_Marginal_Zone_Lymphoma_with_villous_lymphocytes_exome_sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from ~3 Splenic Marginal Zone Lymphoma with villous lymphocytes samples and matched normal DNA from the same patients. Samples will be multiplexed in one lane of Illumina HiSeq. Sequencing to a coverage of at least 30x will be performed and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes.

  Study EGAS00001000139

• Acute_Myeloid_Leukemia_Sequencing

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 25 acute myeloid leukemia samples and subjected to total of eight lanes of 37 bp, paired end sequencing on the llumina GA. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000209

• Comprehensive investigation of genome architecture of papillary thyroid cancer with whole-exon sequencing in the Chinese population.

  In this study, we performed whole-exon sequencing (WES) of 50 paired PTC tumors and adjacent normal tissues to identify novel potential biomarkers. We extracted mutational signatures which induce somatic mutations. Moreover, we observed copy number changes frequently occurring in some cancer related genes. Our study covers a comprehensive genetic framework that can be used in clinical trials and treatment modalities in PTC.

  Study EGAS00001002402

• Targeted sequencing DDR genes in cancer stem cells

  Colorectal cancer stem cells (CSCs) show heterogeneous levels of constitutive replication stress leading distinct dependence on the replication stress response. The aim of the projects was to find genetic, epigenetic, phenotypic factors associated with the resistance of colorectal CSCs to inhibitors of the ATR/CHK1 pathway, which regulates of the replication stress response. Different pairs of colorectal CSCs sensitive and resistant to ATR or CHK1 inhibitors were analyzed

  Study EGAS00001004892

• TP53 variant detection analysis in high grade serous epithelial ovarian cancer

  The aim of this study was to detect in the DNA purified from PAP test samples collected years before the diagnosis of high grade serous epithelial ovarian cancer the presence of the clonal pathogenic TP53 variant identified in the matched primary tumor biopsy. In this specific part of the study, we analyzed FFPE tumor samples to identify clonal pathogenic variants to be tested in matched PAP tests.

  Study EGAS00001004361

• Whole genome sequencing of tumour and matched normal from patients with family history of breast cancer

  Analysis of whole genome sequencing of tumour and matched normal from familial breast cancer patients who had previously undergone clinical germline testing for variation in the BRCA1 and BRCA2 genes. The patients were either carriers of BRCA1 or BRCA2 germline pathogenic variants or non-carriers high-risk individuals (non-BRCA1/2). Somatic mutational signatures were used to study tumour aetiology of these individuals.

  Study EGAS00001003305

• Targeted sequencing of 72 prostate cancer driver in 712 plasma cell free DNA samples

  Dataset contains targeted sequencing data of 712 plasma cell free DNA samples and 428 white blood cell samples collected from 428 men with metastatic prostate cancer. Target capture was performed using a hydridization-based custom Roche SeqCap EZ Choice kit, designed to capture all exons of 72 prostate cancer driver genes. Cell free DNA was extracted from 10 mL blood samples. Libraries were sequenced using Illumina HiSeq 2500 or Illumina MiSeq instruments to a median coverage of 750x. 62% of samples had ctDNA fraction above 2% of total cfDNA. Note that "Dataset type" is erroneously listed as "Amplicon sequencing", because "Captured-based targeted sequencing" or "Hybridization-based targeted sequencing" were not available options in EGA at the time of submission.

  Dataset EGAD00001004208

• Platinum Pedigree Consortium Long-Read Sequencing

  Platinum Pedigree Consortium includes whole genome sequencing of blood-derived DNA using five technologies on a 4-generation family. This is the CEPH-Utah (CEU) family 1463 and includes 4 grandparents from 1st generation, 2 parents from 2nd generation, 5 children from 3rd generation, 9 individuals from the 4th generation representing 2 branches of the 3rd generation, and their 2 additional parents. Family was not selected for disease, rather large size to study genetic transmission and human variation.Data available through dbGaP include raw sequence data: PacBio HiFi reads in unaligned BAM formats, Ultra-Long Oxford Nanopore (ONT) reads in FASTQ formats, Illumina sequencing, strand-seq and Element sequencing data in FASTQ format. Additionally, alignment files for HiFi reads mapped to the GRCh38 and CHM13v2.0 reference genomes, as well as de novo genome assemblies generated for this project are included.

  Study phs003793

• Single Cell DNA Methylation Analysis for Forensic Epigenetics

  As part of the Epigenetic CHaracterization and Observation (ECHO) program, the Genomic Analysis Laboratory at the Salk Institute generated the DNA methylation profiles of certain PBMC cell types to determine the change in methylation levels before, during or after exposure to certain biological or chemical agents. Samples from individuals who either handled anthrax in controlled environments or who tested positive to MRSA, MSSA, HIV, COVID-19 or exposed to Flu virus or organophosphates, or control samples were used in single-nucleus methylation (snmC-seq) assays to quantify DNA methylation levels of cytosine residues of the DNA. Around 5-10% cytosine sites were sampled in the assay. Using computational analyses, regions in the genome differentially methylated in response to the exposure were identified. This information can be used to develop diagnostic tools to predict the type of infection or time since exposure.

  Study phs003204

• H3K27ac ChIP-seq in primary inflammatory macrophages from 2 minor allele homozygotes and 2 major allele homozygotes at rs2836882

  This dataset consists of H3K27ac ChIP-sequencing in inflammatory (TPP) macrophages from 2 minor allele homozygotes and 2 major allele homozygotes at rs2836882. Monocytes were positively selected from PBMC using CD14 Microbeads and inflammatory macrophage differentiation performed using conditions that model chronic inflammation (TPP): 3 days GM-CSF (50ng/mL) followed by 3 days GM-CSF, TNFa (50ng/mL), PGE2 (1mg/mL), and Pam3CSK4 (1mg/mL). After harvesting, cells were cross-linked, quenched, lysed, and sheared. Immunoprecipitation of histone-DNA complexes was performed overnight at 4C with rotation using an anti-H3K27ac antibody and the SimpleChIP Plus Sonication ChIP kit (Cell Signaling Technology). Following reverse cross-linking, 50ng of immunoprecipitated DNA or input DNA were used to prepare sequencing libraries using the iDeal Library Preparation kit (Diagenode), according to manufacturer instructions. 10 PCR cycles were used for the amplification step and size selection was not performed. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 (Agilent) and the libraries were sequenced in pools of 8, with each pool being sequenced in 2 lanes of an Illumina HiSeq2500 high output flow-cell (50bp, single-end reads). Raw data are provided as raw and aligned single-end sequencing reads from H3K27ac-bound DNA and the input chromatin. Raw reads were trimmed using Trim Galore and aligned to the reference human genome (hg19) using Burrows-Wheeler Aligner (v0.7.12) with default parameters. Aligned reads were converted to BAM files, sorted, and technical duplicates merged before indexing – all using SAMtools (v1.4). PCR duplicates were identified using Picard tools (v2.18.1) and removed together with unmapped reads using SAMtools (v1.4). The resulting BAM files were re-sorted and indexed after filtering.

  Dataset EGAD00001011351

• A Genomic Atlas of Systemic Interindividual Epigenetic Variation in Humans (GTEx)

  Methylation of cytosines in CpG dinucleotides is an epigenetic mechanism with essential roles in mammalian development. To explore its functions in cellular differentiation, unbiased analysis of CpG methylation by whole genome bisulfite sequencing (WGBS) has been used to characterize epigenetic differences among different human tissues and cell types. Meanwhile, human interindividual variation in DNA methylation that is not cell-type specific has attracted relatively little attention. Systemic interindividual epigenetic variation is important, however, because like genetic variation it is a potential determinant of phenotypic variation and can be assessed in any easily obtainable DNA sample. Since systemic epigenetic variants originate in the preimplantation embryo, their establishment can be influenced by periconceptional environment, and potentially provide information about lifetime risks relevant to global health, obesity, and cancer. We elucidated systemic interindividual variation in CpG methylation in the human genome. We studied brain, heart, and thyroid tissues (representing all three germ layer lineages) from each of 10 donors in the NIH Gene-Tissue Expression (GTEx) project. We performed deep whole genome bisulfite sequencing for these 30 samples, achieving a sequencing depth of over 50x coverage per sample. We identified 9,926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, often correlate with one another over long genomic distances, are associated with transposable elements and subtelomeric regions, conserved across various human ethnic groups, and particularly sensitive to periconceptional environment. While genetic variation appears to influence methylation at most CoRSIVs, many show no evidence of genetic influence, suggestive of 'pure' epigenetic variation. At CoRSIVs, interindividual variation in DNA methylation in an easily biopsied tissue predicts expression in other tissues, and genes associated with these loci are implicated in a range of human disorders. In addition to charting a previously unrecognized molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease.Version 2 now also includes Target Capture Sequencing of CoRSIVs in 808 tissues (188 GTEx Donors). Focusing on the CoRSIVs identified by analyzing WGBS data, a Target Capture Bisulfite sequencing assay was developed. Using the genotype data of 188 GTEx donors, we assessed mQTL by capturing a 1MB region at each CoRSIV and quantifying methylation by Bisulfite-seq. The Target Capture Bisulfite sequencing data will be available to download via the AnVIL project.

  Study phs001746

• NINDS Deep Sequencing for the Detection of Viral Sequences in Primary Progressive Multiple Sclerosis Brains

  Deep sequencing allows for a rapid, accurate characterization of microbial DNA and RNA sequences in many types of samples. Deep sequencing (also called next generation sequencing or NGS) is being developed to assist with the diagnosis of a wide variety of infectious diseases. In this study, seven frozen brain samples (n = 7) from deceased subjects with recent encephalitis were investigated. RNA from each sample was extracted, randomly reverse transcribed, and sequenced. The sequence analysis was performed in a blinded fashion and confirmed with pathogen-specific PCR. This analysis successfully identified measles virus sequences in two brain samples and herpes simplex virus type-1 sequences in three brain samples. No pathogen was identified in the other two brain specimens. These results were concordant with pathogen-specific PCR and partially concordant with prior neuropathological examinations, demonstrating that deep sequencing can accurately identify viral infections in frozen brain tissue (Chan et al., 2014). Data from the primary progressive multiple sclerosis (PPMS) brain specimens (n = 14) and Normal Control brain specimens (n = 14) are also submitted here. All the subjects studied here (encephalitis, PPMS, and controls) were selected from existing collections at the Rocky Mountain and UCLA brain banks. These selections were performed by the directors at the two centers (Dr. Corboy at RM and Nagra at UCLA) based on clinic information provided at the time of collection. All the specimens are from deidentified deceased individuals. The submitting investigators have no identifying information on any of these subjects. To avoid confusion, the dbGaP Subject IDs are identical to the brain bank identifying numbers.

  Study phs000715

• Integration of Genomics and Transcriptomics in unselected Twins and in Major Depression

  Our goals are to develop a comprehensive understanding of the genomics of transcription in a population based unselected sample and to discover DNA and RNA biomarkers for major depressive disorder (MDD). This work is essential to developing a more complete understanding of the biological basis of MDD, a common complex trait associated with considerable morbidity, mortality, and personal/societal cost. All biological samples have been collected from well-defined populations, and are now available. First, we conduct a "genetical genomics" or eQTL study of ~800 MZ and ~800DZ twin pairs. Each subject has been assayed for genome-wide SNPs and CNVs and gene expression from peripheral blood sampled under standardized conditions. We determine the genetic architecture (genetic and non-genetic proportions of variance via twin analyses) for every transcript, and the genome-wide associations (i.e., SNP-transcript eQTL pairs). These analyses will be expanded to consider transcriptional modules. The key deliverable is a detailed catalogue of the general and specific architecture of transcription plus raw intensity files. Second, we seek to discover DNA and RNA biomarkers relevant to MDD, capitalizing on the results of a large MDD study with repeated clinical and biological assessments; we have previously shown that PB is a reasonable proxy for CNS expression and employ an advanced modelling framework: (a) Using baseline data, we identify biomarkers for MDD by comparing ~1000 controls with ~1400 MDD cases via comparisons of SNP, CNV, expression transcripts, and transcriptional modules. (b) Using longitudinal data, we contrast gene expression signatures assessed at baseline and two years later in ~200 controls and ~500 MDD cases.

  Study phs000486

• Transcriptional Response to Hypoxia in iPSC-Derived Endothelial Cells from a High Altitude Adapted Population

  We established lymphoblastoid cell lines from 10 adult individuals of Tibetan ancestry living in the Chicago area. These lines were reprogrammed to induced pluripotent stem cells (iPSC). We validated genetic ancestry by genome-wide SNP array genotyping and population genetic analyses. After being subjected to standard quality control testing iPSCs were differentiated into endothelial cells. Following differentiation, endothelial cells were isolated via a pull down protocol using beads coated with an antibody for a canonical surface cell marker of the vascular endothelium (CD144). Purified vascular endothelial cells were cultured in parallel in normoxia (20% O2) and hypoxia (1% O2) for 48 hours prior to harvesting and processing for bulk RNA-sequencing. We provide imputed genotype data and bulk RNA-sequencing data in normoxia and in hypoxia for each of the 10 individuals. We also provide multiplexed scRNA-sequencing data for the 10 Tibetan individuals pooled with 10 CHB individuals from the 1000 Genome Project. Additionally, we provide scRNAseq data for the cardiomyocytes derived from the same iPSC lines from the Tibetan individuals pooled together with cardiomyocytes derived from iPSC lines of 10 CHB individuals from the 1000 Genome Project. Lymphoblastoid cell lines from the CHB were reprogrammed to iPSCs and differentiated to cardiomyocytes using the same protocols as used for the Tibetans. The batches of 4 lines were balanced by sex and population. These iPSC-derived cardiomyocytes were cultured in hypoxia (1% O2) for 48 hours and subjected to scRNAseq in pooled batches of 3 or 4 lines. The CHB individuals included in this analysis were: NA18528, NA18531, NA18557, NA18596, NA18606, NA18608, NA18614, NA18619, NA18633, and NA18748.

  Study phs003758

• The light chain IgLV3-21 defines a new poor prognostic subgroup in Chronic Lymphocytic Leukemia: results from a multicenter study

  Purpose: Unmutated (UM) immunoglobulin heavy chain region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL). Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21 which is potentially able to trigger cell-autonomous BCR-mediated signaling. However this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: we performed total RNA sequencing to characterize IgLV3-21 patients (n=32) and investigated IgLV3-21 prognostic impact in terms of treatment-free (TFS) and overall (OS) survival in 3 other independent cohorts for a total of 813 patients where IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients present higher expression of genes responsible for ribosome biogenesis and translation initiation (P<0.0001) and MYC target genes (P=0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P<0.05), in particular in IgHV mutated patients. In each of the 3 independent validation cohorts (n=813), we showed that IgLV3-21 rearrangements -similar to UM IgHV status- conferred poor prognosis compared to mutated IgHV (P<0.0001). Importantly, we confirmed in multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P<0.0001). Conclusions: We therefore demonstrate for the first time that a light chain can impact on CLL prognosis and that IgLV3-21 light chain usage defines a new poor prognostic subgroup in CLL.

  Study EGAS00001002894

• Transcriptional_profiling_of_tauopathies_in_human_IPS_derived_neurons

  This project is a pilot study, in collaboration with Maria Grazia Spillantini and Mariangela Iovino (Cambridge Centre for Brain Repair), to investigate the utility of IPS-derived neurons for the study of neurodegenerative disorders. Our aim is to characterise the transcriptional consequences of tauopathies using neurons derived from differentiated IPSCs as a model system. We will use IPS cells derived from six individuals, four with known mutations in the tau protein, 2 without. RNA will be extracted at Day 0 and Day 65 of differentiation by which time the neuronal tauopathy is apparent. RNA will be extracted and the transcriptome of each line characterised using RNAseq. We will then search for genes that are differentially expressed between the transcriptomes of individuals with tau mutations versus those in controls. My lab will analyse the RNAseq data, comparing both affected and controls and both time-points, to establish candidate genes. Darren Logan’s lab, along with our collaborators, will experimentally verify and further investigate these genes in additional lines and animal models. From this analysis we will generate a list of candidate genes that are differentially expressed between cases and controls. This study will not only help us understand the molecular basis of tauopathies, but also identify gene candidates for biomarkers of neurodegenerative disease. It will serve as a proof of principle for future planned studies into generating and transcriptomically analysing an allelic series of Tau mutations in IPSCs with a controlled genetic background.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 EGAS00001000382

• Targeting FGFR1 for treatment of soft-tissue sarcoma (H021)

  Purpose: Altered FGFR1 signaling has emerged as therapeutic target in various epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties and potential as drug target of FGFR1 in STS.Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by fluorescence in situ hybridization, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three independent patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using short-term viability assays, long-term colony formation assays, and biochemical analysis.Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; Cohort 1), 13 of 79 (16.5%; Cohort 2), and 80 of 254 (31.5%; Cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, Cohort 2) and 39 of 254 (15.4%; Cohort 3) patients. Targeting of FGFR1 by short hairpin RNA-mediated knockdown and different small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is primarily dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway.Conclusion: These data identify FGFR1 as driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as therapeutic option in this challenging group of diseases.H021

  Study EGAS00001001844

• 18 Whole Exome Sequencing for Radiation Induced-Meningiomas

  Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs.Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in sporadic meningiomas. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.

  Study EGAS00001002317

• Transcriptomics-driven classification of ALAL

  Acute leukemia of ambiguous lineage (ALAL) is a rare, poor-prognosis subtype of acute leukemia that cannot be assigned to a single hematopoietic lineage. Although ALAL patients are typically treated with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) regimens, optimal treatment choice is hindered by their lineage ambiguity. Therefore, we investigated the added value of transcriptomics for improving lineage assignment, currently based mainly on surface markers. First, we used an in-house pipeline to comprehensively detect genetic lesions in RNA-sequencing data (n=23) with a sensitivity >90%, as confirmed by targeted DNA sequencing. Second, we compared ALAL gene expression profiles (GEPs) with representative AML (n=145), B-ALL (n=223) and T-ALL (n=85) cases. In a principal component analysis, ALALs did not form a separate group, but clustered with AML, B-ALL or T-ALL. Accordingly, a machine learning classifier trained with GEPs of acute leukemias segregated 20/23 ALALs into myeloid-, B- or T-lymphoid leukemia. These 20 cases harbored genetic abnormalities consistent with the classifier-assigned leukemia. Furthermore, ALAL GEPs were deconvoluted with single-cell transcriptional profiles of normal hematopoietic cells using CIBERSORTx, revealing enrichment for signatures of lineages corresponding to the leukemic type predicted by our algorithm. The classifier was validated on an external ALAL cohort (n=24), assigning 75% of the patients to a lineage matching their immunophenotypic and methylation profiles. In conclusion, integrative analysis of RNA-sequencing data can accurately classify most ALAL cases. The pipeline and classifier developed in our study are valuable tools to improve ALAL diagnosis and guide therapeutic decisions.

  Study EGAS00001007967

• Profiling of 27 type 2 diabetes GWAS loci using next-generation (NG) capture C in a human beta-cell model

  Most type 2 diabetes association signals are due to variants that impact gene regulation but identifying the genes they impact is challenging. We generated interaction profiles at 27 T2D GWAS loci using next-generation (NG) capture C (6 replicates) in the human beta-cell model, EndoC-betaH1, along with chromatin accessibility profiling using ATAC-Seq (9 replicates).

  Dataset EGAD00001008655

• Epigenomic timecourse of brain organoid development

  Single-cell Cut&Tag of three histone modifications and chromatin accessibility over a timecourse of brain organoid development from pluripotency. We profiled 5 time points of brain organoid development and 2 time points of retinal organoid development. At each time point used scCut&Tag to profile histone modifications (H3K27me3, H3K27ac, H3K4me3) as well as multiome-seq (10X) to jointly profile transcriptome and chromatin accessibility from the same cell suspension. Library preparation was carried out with the 10x genomics platform.

  Dataset EGAD50000000222

• FASTQ Data from In Situ Hi-C on Medulloblastoma Tissue Samples

  29 Hi-C datasets [8 G3 (MB3667, MB3687, MB3690, MB3692, MB3693, MB4010, MB4037, MB4141), 13 G4 (MB0558, MB3510, MB3670, MB3689, MB3716, MB3760, MB3761, MB3807, MB4079, MB4132, MB4174, MBSF7, SNC_2_5), 7 SHH (MB3612, MB3661, MB3662, MB3695, MB3697, MB3724, MB4143), and 1 WNT (MB4036)]. Fresh tissue samples were obtained from The Hospital for Sick Children (Toronto, ON). In situ Hi-C libraries were generated using approximately 2.5 million dissociated cells as input. All Hi-C libraries were sequenced at 150 bp PE with a Hi-Seq X instrument (Illumina) at McGill Genome Centre (Montreal, QC).

  Dataset EGAD50000000771

• Chromatin profiling of baseline and Notch inhibitor treated HCC PDX model

  We generated chromatin accessibility profiles for anti-Notch2 (n=3) and anti-gD (n=3) treated LIV78 tumors. Tumors were isolated, snap frozen in liquid nitrogen and stored at -80C. Tumor tissue was pulverized using a Covaris CP02 CryoPrep Pulverizer. Flash frozen pulverized tumor samples were sent to Active Motif to perform the ATAC-seq assay. Resulting material was quantified using the KAPA Library Quantification Kit for Illumina platforms (KAPA Biosystems), and sequenced with PE42 sequencing on the NextSeq 500 sequencer (Illumina) to produce FASTQ sequencing files.

  Dataset EGAD50000000735

• bulk TCR-seq data IMCISION

  We performed bulk TCR sequencing (Adaptive Biotechnologies, Seattle, WA) on peripheral blood monocytic cells (PBMCs) from 9 HNSCC patients enrolled in the IMCISION trial (Vos et al. 2021) that responded to anti-PD-1 and anti-CTLA4 combination immunotherapy. DNA was extracted from PBMCs that were isolated from pre-treatment and on-treatment blood.

  Study EGAS00001007367

• ATAC-seq in hiPSC-derived neurons after BDNF and KCl stimulations

  Brain-Derived Neurotrophic Factor (BDNF) is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. Molecular mechanisms of BDNF promoting cellular survival and synaptic plasticity have been intensely studied, yet its role in genome regulation is obscure. Using human induced pluripotent stem cell (hiPSC)-derived neurons via lentiviral delivery of the neuronal transcription factor Ngn2, we performed a temporal profiling (1h, 6h and 10h) of chromatin accessibility upon BDNF treatment or depolarization (KCl) to identify BDNF-specific chromatin-to-gene expression programs.

  Dataset EGAD00001009100

• LCM-ATACseq on human lung macrophages

  In this study we employed Laser Capture Microdissection (LCM) for the multimodal profiling of lung macrophages cell populations as a function of location within the healthy tissue. In detail, macrophage mini-bulks (~100 cells) were collected from 4 healthy human donors in 5 different locations of the airways (a total of 20 biopsies), including parenchyma (L1 – lower left lobe (LLL); L6 – 80% distance from LLL tip), trachea (L2), bronchi (L3 – 1st/2nd generation; L5 – 3rd/4th generation), and processed for ATAC-seq.

  Dataset EGAD00001008693

• National Cancer Institute Genome-Wide Association Study of Renal Cell Carcinoma

  The National Cancer Institute (NCI) genome-wide association study (GWAS) of renal cell carcinoma (RCC) was conducted to investigate common genetic variants associated with RCC risk. The GWAS includes 1,453 RCC cases and 3,531 controls of European background from 4 studies (3 cohort, 1 case-control), scanned using the Illumina InfiniumHumanHap 550, 610 and 660W chips. This project was supported by the Intramural Research Program of the National Institutes of Health and NCI. Data from this GWAS were pooled with those from another GWAS of RCC (2,639 cases and 5,392 controls) conducted in Europe by the International Agency for Research on Cancer and the Centre National de Gènotypage. Findings from this collaboration are described in an upcoming report (Purdue et al. Nature Genetics 2011;43(1):60-65; PMID: 21131975). Only data from the NCI scan are included in this dbGaP submission.

  Study phs000351

• A Pilot Study of Neoadjuvant Nivolumab, Ipilimumab and Intralesional Oncolytic Virotherapy for HER2-Negative Breast Cancer

  This study was a single arm phase 1 trial that assessed the regimen safety and feasibility as well as tumor response in patients with localized HER2-negative breast cancer treated with talimogene laherparepvec (T-VEC) in combination with nivolumab and ipilimumab. The primary objective was to evaluate the safety and adverse event profile of this treatment combination. Six patients were enrolled, four having relapses after prior neoadjuvant chemotherapy, and two who were previously untreated. One patient had a pathological complete response, three patients had pathological partial responses, one showed no significant response, and one had disease progression. Biopsies demonstrated increased immune cell infiltration in samples from patients who responded to therapy. In this study, the checkpoint blockade immunotherapy combined with T-VEC provided responses in patients with advanced or relapsed HER2-negative breast cancer at the expense of long-term toxicities.

  Study phs003316

• Whole-genome sequencing of BRCA-mutant breast cancer patient samples from tumour, germline tissue and plasma

  The use of circulating tumor DNA (ctDNA) to profile mutational signatures presents a non-invasive opportunity for understanding cancer mutational processes. In this study we developed MisMatchFinder, a liquid biopsy approach for mutational signature detection using low- coverage whole-genome sequencing of ctDNA. Through analysis of plasma samples across multiple different cancers, we demonstrated that MisMatchFinder accurately infers single-base and doublet-base substitutions as well as indels to enhance detection of ctDNA and clinically relevant mutational signatures. This study contains fastq files from whole-genome sequencing of temporally matched tumour (fresh frozen biopsies), blood germline and plasma samples collected from a BRCA1-mutant breast cancer patient to directly compare mutation signature analysis using gold-standard tumour-germline paired variant calling with our novel ctDNA-based method (MisMatchFinder).

  Study EGAS50000000569

• Methylation-Based Immune Deconvolution in Prostate Cancer Patients Before and After Radical Prostatectomy

  To explore whether surgical treatment for prostate cancer leads to long-term immune changes, we conducted a pilot study of n=11 prostate cancer patients treated with radical prostatectomy. We also included n=8 patients managed with active surveillance as a comparison group. We examined intra-individual changes in circulating immune cell subsets using serial blood samples collected pre- and approximately 6-months post-prostatectomy, and from matched time points for the patients managed on active surveillance. Immune cell subsets were deconvoluted using genome-wide methylation data. We observed no meaningful changes in circulating immune cell subsets in either patient group, suggesting that any surgery-induced immune changes to the circulating immune profile may not be long-lasting. The genome-wide methylation data from the two time points will be made available through dbGaP.

  Study phs003660

• Human papillomavirus integration induces oncogenic host gene fusions in oropharyngeal cancers

  HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host gene fusions, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of E6 and E7, thereby increasing oncoprotein abundance. We conclude that expression of HPV16 oncoproteins and host gene fusions generated from HPV integration sites can be sufficient for cancer development.

  Study EGAS50000000892

• Integrative genomic analyses reveal androgen-driven somatic alteration landscape in early-onset prostate cancer

  Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in eleven tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of >10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA.

  Study EGAS00001000400

• Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer

  A subset of Cancer-Associated Fibroblasts (CAF-S1) mediates immunosuppression in breast cancers (BC), but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 18000 single CAF-S1 fibroblasts from BC. We validate the 5 most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extra-cellular matrix proteins and TGF signaling respectively, are indicative of primary resistance to immunotherapies. Cluster 0 up-regulates PD-1 and CTLA-4 protein levels in regulatory T lymphocytes (Tregs), which in turn increases CAF-S1 cluster 3 cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.

  Study EGAS00001004030

• Hereditary Cancer Diagnostics with I2HCP gene panel

  This dataset contains targetted DNA sequencing data generated in the context of genetic diagnostics of hereditary cancer. Target enrichment was performed with the I2HCP, a custom hereditary cancer gene panel based in Agilent SureSelect and developed by the Germans Trias i Pujol Research Institute (IGTP, Badalona, Catalonia, Spain) and the Catalan Institute of Oncology (ICO, L'Hospitalet de Llobregat, Catalonia, Spain). After the enrichment, 108 samples were sequenced in Illumina HiSeq machines and 130 in MiSeq machines. Some of the samples were sequenced on both platforms. The dataset also includes MLPA validation data for all identified copy-number alterations, annotated with exon resolution and information about negative MLPA results. All this data was generated in the context of routine diagnostics and compiled together with MPLA validation data for a genetic diagnostics oriented benchmark of germline CNV calling tools.

  Study EGAS00001004316

• Chromothripsis followed by circular recombination drives oncogene amplification in human cancer

  The mechanisms behind the evolution of complex genomic amplifications in cancer have remained largely unclear. We here identified a type of amplification, termed as “seismic amplification”, that is characterized by multiple rearrangements and discontinuous copy number levels. Seismic amplifications occurred in 9.9% (274/2,756) of cases across 38 cancer types and were associated with massively increased copy numbers and elevated oncogene expression. Reconstruction of the development of seismic amplification revealed a stepwise evolution, starting with a chromothripsis event, followed by formation of circular extrachromosomal DNA that subsequently underwent repetitive rounds of circular recombination. The resulting amplicons persisted as extrachromosomal DNA circles or had reintegrated into the genome in overt tumors. Together, our data indicate that the sequential occurrence of chromothripsis and circular recombination drives oncogene amplification and over-expression in a substantial fraction of human malignancies.

  Study EGAS00001005424

• Application of high-throughput, high-depth, targeted single-nucleus DNA sequencing in pancreatic cancer

  Despite insights gained by bulk DNA sequencing of cancer it remains challenging to resolve the admixture of normal and tumor cells, and/or of distinct tumor subclones; high throughput single-cell DNA sequencing circumvents these and brings cancer genomic studies to higher resolution. However, its application has been limited to liquid tumors or a small batch of solid tumors, mainly because of the lack of a scalable workflow to process solid tumor samples. Here we optimized a highly automated nuclei extraction workflow that achieved fast and reliable targeted single-nucleus DNA library preparation of 38 samples from 16 pancreatic ductal adenocarcinoma (PDAC) patients, with an average library yield per sample of 2867 single nuclei. We demonstrate that this workflow not only performs well using low cellularity or low tumor purity samples but reveals novel genomic evolution patterns of PDAC as well.

  Study EGAS00001006024

• Characterization of Cell Free Plasma Methyl-DNA From Xenografted Tumors to Guide the Selection of Diagnostic Markers for Early-Stage Cancers

  Circulating cell-free methyl-DNA (mcfDNA) contains promising cancer markers but its low abundance and possibly diverse origin pose challenges toward the accurate diagnosis of early stage cancers. By whole-genome bisulfite sequencing (WGBS) of cell-free DNA (cfDNA) from about 0.5 mL plasma of mice xenografted with human tumors, we obtained and aligned the reads to the human genome, filtered out the mouse and carrier bacterial sequences, and confirmed the tumor origin of methyl-cfDNA (mctDNA) by methylation-sensitive restriction enzyme digestion prior to species-specific PCR. We estimated that human tumor-specific reads (ctDNA) or mctDNA comprised about 0.29 or 0.01%, respectively of the xenograft mouse cfDNA, and about 0.029 or 0.001% of the cfDNA of human early stage cancer patients. Similar WGBS of early stage (0-II, node- and metastasis-free) breast, lung or colorectal cancer samples identified hundreds of specific DMRs (differentially methylated regions) compared to healthy controls. Their association with tumourigenesis was supported by stage-dependent methylation, tumor suppressor or oncogene clusters, and genes also identified in the xenograft samples. Using 20 three-cancer-common and 17 colorectal cancer-specific DMRs in combination (top 0.0018% of the WGBS methylation clusters) was sufficient to distinguish the stage I colorectal cancers from breast and lung cancers and healthy controls. Our data thus confirmed the tumor origin of mctDNA by sequence specificity, and provide a selection threshold for authentic tumor mctDNA markers toward precise diagnosis of early stage cancers solely by top DMRs in combination.

  Dataset EGAD00001008696

• Comprehensive benchmarking of methods for mutation calling in circulating tumor DNA

  This study provides a comprehensive benchmarking resource for somatic variant detection in cell-free DNA (cfDNA) from cancer patients. Longitudinal plasma samples from colorectal and breast cancer cohorts were selected to create patient-matched dilution series spanning ultra-low to high circulating-tumour-DNA (ctDNA) fractions, while preserving each individual’s germline and clonal haematopoiesis background. Deep whole-genome sequencing (150×) and ultra-deep whole-exome sequencing (2,000×) generated a reference call set of ~37,000 single-nucleotide variants and ~58,000 insertions/deletions. These data enabled systematic evaluation of nine somatic variant callers across variable ctDNA levels and sequencing depths, and were further used to explore machine-learning–guided parameter tuning. The resulting dataset offers an openly accessible framework for developers and clinicians to assess and optimize somatic variant calling in liquid biopsy applications.

  Study EGAS50000001313

• Small cell cancer NDS Oxford DAC

  Dac EGAC00001003350

• Cancer Team Data Access Committee

  Dac EGAC00001002762

• Small cell cancer NDS Oxford DAC

  Dac EGAC00001003343

• Asian lung cancer genome data

  Dac EGAC00001000248

• MCCB Breast Cancer Data Access Committee

  Dac EGAC00001000854

• Rectal Cancer Samples Data Access Committee

  Dac EGAC00001001034