9182 results for "cancer rna-seq"

in 108.55 milliseconds.

• cfMeDIP data for 22 WCDT samples

  We analyzed the cell free DNA methylomes using 22 plasma samples from patients with mCRPC prostate cancer in the WCDT project. Methylation was profiled using the methylated DNA immunoprecipitation coupled to next generation sequencing (MeDIP) technology.

  Dataset EGAD00001008713

• Sequencing data for oesophageal and related samples - Katz-Summercorn, Jammula et al (WGS)

  Data supporting: “Multi-omic cross-sectional cohort study of pre-malignant Barrett’s esophagus reveals structural variation and retrotransposon activity occur early in cancer evolution.” Katz-Summercorn, Jammula et al. WGS (BAM files)

  Dataset EGAD00001006349

• Genome and transcriptome sequence data from a metastatic squamous cell carcinoma of the cervix patient

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

  Dataset EGAD00001004616

• Genome and transcriptome sequence data from a metastatic high-grade adenocarcinoma of the fallopian tubes patient

  Genome and transcriptome sequence data from a metastatic high-grade adenocarcinoma of the fallopian tubes patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001004709

• Genome and transcriptome sequence data from a tongue squamous cell carcinoma (head and neck) patient

  Genome and transcriptome sequence data from a tongue squamous cell carcinoma (head and neck) patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001005865

• Genome and transcriptome sequence data from a spindle cell carcinoma of the left parotid patient

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

  Dataset EGAD00001003734

• Genome and transcriptome sequence data from a metastatic squamous cell carcinoma of the cheek patient

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

  Dataset EGAD00001004603

• Genome and transcriptome sequence data from a clear cell carcinoma of the left ovary patient

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

  Dataset EGAD00001004608

• Genome and transcriptome sequence data from a metastatic clear cell carcinoma of the ovary patient

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

  Dataset EGAD00001004661

• Genome and transcriptome sequence data from a small cell/neuroendocrine carcinoma of the lung patient

  Genome and transcriptome sequence data from a small cell/neuroendocrine carcinoma of the lung patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002617

• Genome and transcriptome sequence data from a metastatic adenocarcinoma of unknown primary (upper GI?) patient

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

  Dataset EGAD00001005837

• Genome and transcriptome sequence data from a metastatic squamous cell carcinoma of the lung patient

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

  Dataset EGAD00001005850

• BLUEPRINT EpiVar ChIP-seq in lineage specifying transcription factors

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise "experimental noise" and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. This data set contains functional genomics data for gene expression and chromatin state.

  Dataset EGAD00001004571

• The University of Hong Kong Colon Cancer GCV Study

  Background: Ganciclovir (GCV) is widely used in solid organ and hematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig¬¬ were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV¬sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

  Study EGAS00001006707

• RRBS sequencing of 7 tumour regions and a normal sample from a single TRACERx patient.

  Background: Epigenetic heterogeneity within a tumour can play an important role in tumour evolution and the emergence of resistance to treatment. It is increasingly recognised that the study of DNA methylation (DNAm) patterns along the genome - so-called `epialleles' - offers greater insight into epigenetic dynamics than conventional analyses which examine DNAm marks individually. Results: We have developed a Bayesian model to infer which epialleles are present in multiple regions of the same tumour. We apply our method to reduced representation bisulfite sequencing (RRBS) data from multiple regions of one lung cancer tumour and a matched normal sample. The model borrows information from all tumour regions to leverage greater statistical power. The total number of epialleles, the epiallele DNAm patterns, and a noise hyperparameter are all automatically inferred from the data. Uncertainty as to which epiallele an observed sequencing read originated from is explicitly incorporated by marginalising over the appropriate posterior densities. The degree to which tumour samples are contaminated with normal tissue can be estimated and corrected for. By tracing the distribution of epialleles throughout the tumour we can infer the phylogenetic history of the tumour, identify epialleles that differ between normal and cancer tissue, and define a measure of global epigenetic disorder. Conclusions: Detection and comparison of epialleles within multiple tumour regions enables phylogenetic analyses, identification of differentially expressed epialleles, and provides a measure of epigenetic heterogeneity.

  Study EGAS00001002484

• RB1 Gene Inactivation by Chromothripsis in Human Retinoblastoma

  Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA. In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.

  Study EGAS00001000598

• Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases

  Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 yr using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2, TP53, RB1, and PTEN, resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers, to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.

  Study EGAS00001003497

• Tissue-specific mutation accumulation in human adult stem cells during life

  Gradual accumulation of mutations in human adult stem cells during life is associated with various age-related diseases, including cancer. The number of stem cell divisions throughout life is believed to be a major determinant for mutation accumulation and could explain the extreme variation of cancer incidence across different organs. Yet, mutation patterns and rates of healthy adult stem cells remain unknown. Here, we determined genome-wide mutation patterns in primary adult stem cells of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years. We find that the number of mutations increases linearly with age up to several thousand mutations per cell at 87 years of age, while mutation spectra remain constant throughout life. Small intestine and colon stem cells have a 2-fold higher mutation rate per year compared with liver stem cells. These differences could be exclusively attributed to the mutagenic action of spontaneous deamination of cytosine residues and may reflect the high stem cell division rate in these tissues. The genomic distribution of somatic mutations is non-random and predominantly associated with DNA replication dynamics in the small intestine and colon, and with transcription in the liver. These results indicate that a stable balance between various mutagenic and DNA repair processes is maintained throughout life and that the activity of these processes in adult stem cells varies between tissues.

  Study EGAS00001001682

• Intra-tumor heterogeneity and clonal evolution of papillary renal cell carcinoma

  Limited knowledge of intratumor heterogeneity (ITH), and clonal evolution of papillary renal cell carcinoma (pRCC) and rare kidney tumor subtypes hinders understanding of tumorigenesis and therapeutic efficacy. We conducted an integrative genomic and epigenomic ITH analysis and studied clonal evolutionary history of pRCC and rare kidney tumor subtypes. We dissected multiple consecutive samples from the center of the tumor towards the tumor's periphery, a normal sample ~5 cm distant from the tumor, and, where feasible, metastatic regions in the adrenal gland. Specifically, we performed 60X multi-region whole-genome sequencing (mWGS), both genome-wide methylation and SNP array profiling, and deep targeted sequencing (average 500X coverage) of 254 cancer driver genes (PMID:24390350). The study population comprises 39 patients with kidney cancers, including 23 with papillary type 1 (pRCC1), 12 with papillary type 2 (pRCC2), one of which also had areas of clear cell, and one each with collecting duct tumor (cdRCC), renal fibrosarcoma rSRC, mixed pRCC1/pRCC2, and an unclassified renal cancer with mixed features of pRCC2 and cdRCC. Based on DNA sample availability, we conducted whole genome sequencing (WGS) on 124 samples from 29 subjects, deep targeted sequencing on 139 samples from 38 subjects, SNP array genotyping on 101 samples from 38 subjects, and genome-wide methylation profiling on 139 samples from 28 subjects. All assays were performed on tumor, metastasis and normal tissue samples, with the exception of the SNP array genotyping, which was conducted only on tumor samples.

  Study phs001573

• MGHBoston_Molpheno_Closed

  This dataset contains Whole Genome Sequencing and, if available, RNA-sequencing and/or ATAC-sequencing data of 17 lymphoblastoid cell lines derived from patients with complex genomic rearrangements. Patients have phenotypes in category of intellectual disability and/or multiple congenital anomalies. Data access is closed.

  Dataset EGAD00001004866

• Cryopreservation of human cancers conserves tumour heterogeneity for single-cell multi-omics analysis

  Single-cell RNA-Sequencing of three primary breast cancers, two primary prostate cancers, and a metastatic melanoma sample from Wu et al. (2021) Genome Medicine study. Each tumour was sequenced across different cryopreservation conditions including Fresh Tissue (FT), cryopreserved single-cell suspensions (CCS), cryopreserved solid tissue fragments (CT) and a cryopreserved after overnight cold storage (CO). Data was generated using the Chromium controller (10X Genomics) and sequenced on the NextSeq platform.

  Dataset EGAD00001007030

• Alloreactive T-cell receptor (TCR) repertoire in kidney transplantation

  We analyzed the T-cell receptor (TCR) repertoires from twelve kidney transplant recipients. Six out of the twelve kidney transplant recipients experienced a cellular rejection after kidney transplantation. TCR repertoires of CD4+ and CD8+ positive T-cells were assessed prior to transplantation and after transplantation at time of allograft biopsy using RNA based T-cell receptor beta next generation sequencing (NGS). In addition, the pre-formed alloreactive TCR repertoire for each kidney transplant recipient was identified using mixed lymphocyte reaction and donor reactive T-cells were subjected to TCR beta sequencing. In two out of the six patients with cellular rejection the TCR repertoire of graft infiltrating T-cells was additionally captured. This dataset comprises a total of 98 samples. NGS TCR beta libraries of all samples were sequenced on an Illumina NextSeq 500 and raw sequencing data (in the form of fastq files) as well assembled clonotypes and their counts (in the form of clonotype tables) are provided.

  Dataset EGAD00001007695

• Single-cell RNA-sequencing of CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) from a Phase I clinical study in paediatric ALL: CARPALL

  Chimeric antigen receptor (CAR)-modified T-cells have become established as an effective treatment of haematological cancers. In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukaemia (B ALL), CD19 targeting CAR T-cells often induce durable remissions. Previously, we generated a novel low-affinity CAR incorporating a CD19-specific single-chain variable fragment (scFV) called CAT, displaying a faster off-rate of interaction than the FMC63 CD19 binder used in prior clinical studies. Here, we systematically analysed CD19 CAR T-cells of ten children with relapsed or refractory B ALL enrolled in the CARPALL trial (NCT02443831). To characterize persisting CD19 CAR T-cells, we performed high throughput single-cell gene expression and T-cell receptor (TCR) sequencing of infusion products and serial blood and bone marrow samples up to five years post-infusion. We isolated CAR T-cells from peripheral blood or bone marrow by flow cytometry for CD3 and CAR expression, prior to single cell sequencing (Chromium 10X) platform.

  Dataset EGAD00001010018

• RNA expression profiling of neuromuscular diseases and viral diseases

  MicroRNAs (miRNAs), particularly those found in human body fluids, have been suggested as potential biomarkers. Among various body fluids, the cerebrospinal fluid (CSF) shows promise as a profiling target for diagnosis and monitoring of neurological diseases. However, relevant genome-scale studies are limited and no studies have profiled exosomal miRNAs in CSF. Therefore, we conducted a next-generation sequencing-based survey of small RNAs in the exosomal and non-exosomal (supernatant) fractions of healthy human CSF as well as serum in each donor. Our data provided the first landscape of small RNAs in CSF exosome.

  Study JGAS000064

• Whole exome sequencing data from non-small-cell lung cancer patients receiving immunotherapy prognosis

  The plasma samples and white blood cell samples were collected from 30 non-small-cell lung cancer patients and 3 healthy individuals. The solid tumor biopsy samples from 14 patients (a subset of the 30 patients) were collected. The cfDNA was extracted from their plasma samples using the QIAamp circulating nucleic acid kit from QIAGEN (Germantown, MD). The cfDNA WES library was constructed with the SureSelect XT HS kit from Agilent Technologies (Santa Clara, CA) according to the manufacturer’s protocol. In brief, 10ng of cfDNA was used as input material. After end repair/dA-tailing of cfDNA, the adaptor was ligated. The ligation product was purified with Ampure XP beads (Beckman-Coulter, Atlanta, GA) and the adaptor-ligated library was amplified with index primer in 10-cycle PCR. The amplified library was purified again with Ampure XP beads, and the amount of amplified DNA was measured using the Qubit 1xdsDNA HS assay kit (ThermoFisher, Waltham, MA). 700-1000 ng of DNA sample was hybridized to the Agilent SureSelect Human All Exon V6 (Agilent) capture library and pulled down by streptavidin-coated beads. After washing the beads, the DNA library captured on the beads was re-amplified with 10-cycle PCR. The final libraries were purified by Ampure XP beads. The library concentration was measured by Qubit, and the quality was further examined with Agilent Bioanalyzer before the final step of 2x150bp paired-end sequencing on the Illumina HiSeq X10 platform (Illumina) at an average coverage of 200. Whole-exome capture libraries of genomic DNA of the 30 non-small cell lung cancer patients were constructed via Roche SeqCap EZ Exome V3 (Roche); whole-exome capture libraries of genomic DNA of the 3 healthy individuals were constructed via Agilent SureSelect Human All Exon V6 (Agilent). Enriched exome libraries were sequenced on the Illumina HiSeq 3000 platform (Illumina) to generate 2x100bp paired-end reads at an average coverage of 200.

  Dataset EGAD00001006096

• Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

  Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients.Data Provider: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC)

  Study EGAS00001000369

• Drug screening and whole genome sequencing of primary cells and cell lines from ovarian cancer patients to associate genomic aberrations with in vitro drug sensitivities

  Identifying drugs for cancers with poor prognosis like ovarian cancer (OC) is hindered by inappropriate cell models and the limitations of current viability assays. We developed an automated confocal microscopy-based live cell assay (DeathPro) that robustly de-convolves cell death and proliferation over time by employing a specific image processing strategy. Using DeathPro, we screened nine OC patient-derived cell lines and one normal cell line (HOSEpiC) with 22 drugs or combinations. Whole genome was performed to analyze if the cell lines harbor OC-typical genomic aberrations and to relate genomic features to drug sensitivities. Commonly observed alterations in OC patients like TP53 mutations and MYC or PI3KCA amplifications were absent in the normal cell line but frequently detected in the OC cell lines. Moreover, genome-derived homologous recombination deficiency (HRD) scores of the OC cell lines correlated with their responses to carboplatin, olaparib and DNA demethylation drugs. Overall, we propose an imaging-based platform to guide drug development and genome-drug sensitivity analysis.

  Study EGAS00001002239

• Genomic and functional fidelity of small cell lung cancer patient-derived xenografts

  Small cell lung cancer (SCLC) patient-derived xenografts (PDXs) can be generated from biopsies or circulating tumor cells (CTCs), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a two-year timeframe, at efficiencies of 89% and 38%, respectively. Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and cisplatin (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient’s disease. Collectively, this work highlights the translational potential of this strategy.

  Study EGAS00001002853

• Comprehensive pharmacogenomic characterization of gastric cancer

  Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

  Study EGAS00001004106

• Genomic analysis and evolutionary modeling of breast and larynx cancer, based on specimens from Polish population

  We explore the genomic characteristics of the original dataset of breast and larynx cancer specimens of several cell types from the collection of the Department of Applied Radiology of the Maria Sklodowska-Curie National Research Institute of Oncology, Krakow (Poland) Branch and Institute of Human Genetics Polish Academy of Sciences. DNA from paired tissue samples from primary tumor locations and concurrent metastasis to regional lymph nodes was sequenced and matched to controls. A range of genomic analyses was carried out, such as estimation of variant allele frequencies (VAF) and copy number variation (CNV). They show that subsets of variants from primary tumors are present in metastatic lymph nodes and that the CNV pattern is similar, but not identical to that known in the literature. In addition to that, we fit the VAF data to theoretical site frequency spectra predicted by multiple models found in the literature. Analysis suggests existence of secondary advantageous subclones arising on the clonal background as well as of a number of neutral or slightly deleterious passenger mutations.

  Study EGAS00001006456

• DERMATLAS__Leiomyosarcoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

  Study EGAS00001007631

• DERMATLAS__Leiomyosarcoma_WES

  irtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

  Study EGAS00001007628

• DERMATLAS__Leiomyoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007629

• DERMATLAS__Leiomyoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007630

• CD8-targeted IL-2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool

  Tumor-specific CD8+ T cells are key effectors of antitumor immunity but are often rendered dysfunctional in the tumor microenvironment. Immune checkpoint blockade can restore antitumor T cell function in some patients, however most do not respond to this therapy, often despite T cell infiltration in their tumors. We here explored a CD8-targeted IL-2 fusion molecule (CD8-IL2) to selectively reactivate intratumoral CD8+ T cells in patient-derived tumor fragments. Treatment with CD8-IL2 broadly armed intratumoral CD8+ T cells with enhanced effector capacity, thereby specifically enabling reinvigoration of the dysfunctional T cell pool to elicit potent immune activity. Notably, the revival of dysfunctional T cells to mediate effector activity by CD8-IL2 depended on simultaneous antigen recognition and was quantitatively and qualitatively superior to that achieved by PD-1 blockade. Finally, CD8-IL2 was able to functionally reinvigorate T cells in tumors resistant to anti-PD-1, underscoring its potential as a novel treatment strategy for cancer patients.

  Study EGAS00001007712

• Ovarian cancer organoid biobank

  Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a novel protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing the spectrum of ovarian neoplasms, including non-malignant borderline tumors, as well as mucinous, clear-cell, endometrioid, low- and high-grade serous carcinomas. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and inter-patient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.

  Study EGAS00001003073

• Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

  The vast majority of colorectal cancer (CRC) patients fail to respond to immune checkpoint inhibitors (ICI). Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve CRC patient outcomes. Here, we demonstrate that transcript levels of the core autophagy gene ATG16L1 are prognostic of poor outcome and predictive of ICI resistance in late-stage CRC. Deletion of Atg16l1 in murine CRC organoids markedly inhibited tumor growth in primary and metastatic niches in syngeneic hosts. ATG16L1 deficiency rendered CRC organoids more responsive to interferon (IFN) signaling and enhanced programmed cell death while decreasing tumor stem-like populations. IFN hypersensitivity consequently promoted cytotoxic anti-tumor immunity in vivo. In IMblaze370, a large phase III clinical trial of anti-PD-L1 in advanced metastatic CRC, low ATG16L1 levels identified patients with increased lymphocyte infiltration and improved outcome in a KRAS mutant setting. This work reveals autophagy as a clinically relevant immunosuppressive mechanism in CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

  Study EGAS00001005952

• 99 Cases of Small Cell Lung Cancer Study

  Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC. The manuscript has been accepted by Plos Genetics.

  Study phs001083

• Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases

  This study is a phase I trial combining ado-trastuzumab emtansine (T-DM1) with Temozolomide (TMZ) for the prevention of additional brain metastases after previous occurrence and local treatment in HER2+ breast cancer patients. Twelve patients were enrolled in this study. Data includes whole exome sequencing (WES) from patients' cerebrospinal fluid (CSF) and plasma samples. The CSF was collected from each patient at trial entry and after the initial two treatment cycles of TMZ and T-DM1 treatment. Blood was collected through a standard peripheral venipuncture at the following four time points: 1) upon trial entry, 2) after two treatment cycles, 3) the treatment cycle prior to the last follow-up, and 4) most recent follow-up. Whole exome libraries were captured by the SureSelect Human All Exon V8 Kit (Agilent, Santa Clara, CA, USA) and sequenced by NovaSeq 6000 S2 Sequencer in paired-end sequencing mode (Illumina, San Diego, CA, USA). Gene mutations in DNMT3A, ELP1, NOTCH4, KMT2B, CRLF2, and KCNJ18 were observed in patients' CSF.

  Study phs003165

• An Isogenic Cell Line Panel for Sequence-based Screening of Targeted Anti-cancer Drugs

  We describe the creation and characterization of an isogenic cell line panel representing common cancer pathways, with multiple features optimized for high-throughput screening. More than 1,800 cell lines from three normal human cells were generated using CRISPR-technologies. Surprisingly, we discovered most of these lines did not result in complete gene inactivation, despite integration of sgRNA at the desired genomic site. However, a subset of the lines harbored true, biallelic disruptions of the targeted tumor suppressor gene, yielding a final panel of 100 well-characterize lines covering 19 pathways frequently subject to loss of function in cancers. This panel included genetic markers optimized for sequence-based ratiometric assays for drug-based screening assays. To illustrate the potential utility of this panel, we developed a multiplexed high-throughput screen that identified Wee1 inhibitor MK-1775 as a selective growth inhibitor of cells with inactivation of TP53. These cell lines and screening approach should prove useful for researchers studying a variety of cellular and biochemical phenomena

  Study EGAS00001005974

• Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocarcinogenesis

  Infection by Hepatitis B Virus (HBV) is the main risk factor for Hepatocellular Carcinoma (HCC) worldwide. HBV can directly drive carcinogenesis through integrations in human genome. This integrative analysis of a French cohort of 190 patients mainly coming from Europe and Africa provides a deep characterization of HBV integrations, in relation with viral and host genomics and clinical features. Clonal HBV integrations directly contribute to HCC development through alterations of cancer driver genes, either at distance when co-localizing with copy number alterations, either locally through viral Enhancers. Together, this analysis gives new insights on HBV-associated driver mechanisms involved in hepato-carcinogenesis.

  Study EGAS00001004629

• CONSERTING: integrating copy number analysis with structural variation detection

  We developed Copy Number Segmentation by Regression Tree in Next Generation Sequencing (CONSERTING), a novel algorithm for detecting somatic copy number alteration (CNA) using whole-genome sequencing (WGS) data. CONSERTING performs iterative analysis of segmentation by read depth change and localized structural variation detection to achieve high accuracy and sensitivity. Analysis of 43 pediatric and adult cancer genomes revealed novel oncogenic CNAs, complex re-arrangements and subclonal CNAs missed by alternative approaches. This study contains all data for "CONSERTING: an accurate method for detecting somatic DNA copy number alterations in whole genome sequencing data", which was previously split between EGAS00001001202 and EGAS00001001050.

  Study EGAS00001001202

• Exome-wide somatic mutation characterization of small bowel adenocarcinoma

  Small intestinal adenocarcinoma (SIA) is a rare and aggressive form of cancer with limited treatment options. To further characterize the somatic mutation landscape of this tumor type, exome sequencing was conducted on a population-based set of SIA samples from all three parts of the small intestine. Archival tissue from 106 tumors with comprehensive clinical patient information entered exome sequencing from a patient series consisting of SIA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify significantly mutated genes from the exome data. Also mutational signature and pathway enrichment analyses were performed.

  Study EGAS00001002559

• Evolution of GBM through therapy

  Primary glioblastoma (GBM) tumours recur following treatment. This is likely due to intratumour heterogeneity (ITH), which reduces the effectiveness of cancer therapies by enabling therapy-driven tumour evolution: Darwinian selection of genotypically and/or phenotypically distinct cells (subclones) that resist treatment to seed regrowth of an even less treatable recurrence. To investigate this we sequenced a pilot cohort of nine paired primary and locally recurrent GBM tumours, alongside matched blood samples, in order to begin characterising therapy resistant cells and thereby infer the mechanisms by which they evaded treatment. These data were included in the first data release from the Glioma Longitudinal AnalySiS (GLASS) consortium.

  Study EGAS00001003546

• Deciphering somatic mosaic structural variation in human blood lineages using single-cell multiomics

  Somatic mosaicism (SM), referring to the presence of somatic mutations in sub-populations of cells within healthy individuals, is associated with an increased risk of a variety of diseases, including cancer. Blood is at particularly high risk of SM, given its rapid turnover and functionally- heterogeneous cell-type composition. While the roles of point mutations and large-scale rearrangements in blood SM have been scrutinised in recent years, the functional impact of mosaic structural variants (mSVs) remains poorly understood. Using haplotype-resolved single-cell multi-omics, we explored the mSV landscape of human hematopoietic stem and progenitor cells (HSPCs).

  Study EGAS00001006567

• Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in ICI-related pneumonitis

  ICI-pneumonitis is a frequent serious adverse event of cancer immunotherapy hinging on a cell-mediated immune response, though the exact pathophysiology is currently unknown. Using single-cell transcriptomics, an enrichment of pathogenic (TBX21, RORC, IFNG, IL17A, CSF2 expressing) T-helper 17.1 cells and pro-inflammatory (TNF, IL1B, IL6, IL23A expressing) monocytes was identified in ICI-pneumonitis bronchoalveolar lavage fluid, putatively engaging in a feedforward inflammatory loop. This finding yields several novel therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.

  Study EGAS00001006762

• Genome-wide genetic and epigenetic dataset of pancreatic acinar cell carcinomas

  Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. To identify potential targets for personalized treatment, integrative genome- and epigenome-wide analyses were performed. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are known. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies potential novel therapeutic targets in ACC for drugs recently approved for precision cancer therapy.

  Study EGAS00001002533

• Genome Landscape of Primary Pancreatic Ductal Adenocarcinoma

  The purpose of the Australian ICGC Pancreatic Cancer Genome Sequencing Initiativestudy is to identify the common driving mutations underlying the initiation anddevelopment of Pancreatic Adenocarcinoma in a large cohort of pancreatic cancerpatients (n=350). Matched genome sequences will be generated from normal tissue(duodenum) and resected primary tumour tissue in each patient using exome andwhole genome sequencing. The complete repertoire of somatic mutations will bedetermined (substitutions, indels, copy number changes and structural changes).Where possible, matched transcriptome sequencing will also be carried out todetermine locus activity, which mutations are actively expressed and whichrearrangements give rise to gene-fusion transcripts.

  Study EGAS00001000154

• Whole Exome Characterization of Squamous Cell Lung Cancers (Lung SQCC) from Appalachian Kentucky (APPKY)

  This is a pilot study of squamous cell lung cancer and matched normal tissue pairs collected (convenience sample) from patients from Central Appalachia, in Southeastern Kentucky. This study performed whole exome sequencing on tumor and matched normal DNA samples from 51 lung squamous cell carcinoma (SQCC) subjects from Appalachian Kentucky (AppKY). Somatic genomic alteration profiles were compared between the AppKY and TCGA SQCC cohorts. We found that IDH1 and PCMTD1 had higher mutation rates in AppKY versus TCGA. These findings suggest population differences in the genetics of lung SQCC between AppKY and US populations that have implications for personalized treatment for this disease.

  Study phs001651

• Bam files from whole exome sequencing (WES)from multiple laser microdissected regions from tumor and paired biopsies from metastatic lesions.

  In this study we characterized genomic alterations in three bladder cancer patients with metastatic disease courses. Multiple regions were procured by laser microdissection or punctures from primary tumor, lymph node metastases and from distant metastases. Data provided here consist of 35 Bam files for WES (32 Tumors and 2 blood, 1 adjacent normal)

  Dataset EGAD00001002772