4984 results for "*oma"

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• RNA-seq of Ewing sarcoma tumors (ICGC)

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

  Study EGAS00001003333

• Whole exome sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003839

• Targeted sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003840

• Osteosarcoma mate-pair and RNA-sequencing

  DNA mate pair and RNA sequencing data of conventional osteosarcomas. Mate pair libraries, with average insert sizes of 2-4 kb, were prepared for sequencing using the Nextera Mate Pair Library Preparation Kit. Paired-end 76 base pair reads were generated using an Illumina NextSeq 500 sequencing instrument. Total RNA was enriched for polyadenylated RNA using magnetic oligo(dT) beads. Enriched RNA was prepared for sequencing using the TruSeq RNA Sample Preparation Kit v2 and paired-end 151 base pair reads were generated from the cDNA libraries using an Illumina NextSeq 500 instrument.

  Study EGAS00001003842

• Whole Exome Sequences from Iberian Roma samples

  Study of high-depth Roma whole exomes to analyse the impact of complex demography on the functional genomic variation. This study also includes genome-wide array data of Iberian Roma individuals

  Study EGAS00001004599

• Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

  Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3'UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NFκB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

  Study EGAS00001002936

• Whole-exome sequencing and microRNA profiling predicted relapse risk of stage I lung adenocarcinomas

  Despite the advance in precision therapy, about 20% of stage I non-small cell lung cancer patients suffer a relapse after surgical resection. To develop molecular signatures for relapse prediction of stage I lung adenocarcinoma (LUAD), we conduct comprehensive analyses of multiplatform molecular profiling from 113 treatment-naïve stage I Taiwanese LUAD patients. We identify 16 nonsynonymous non-sporadic point mutations (NSPOPMs) harbored at EGFR, KRAS, TP53, CTNNB1 and 6 other genes, and find that the Non-EGFR NSPOPMs were associated with early relapse in a dose-dependent manner via variant allele fraction (VAF). We define a score, maxVAF, to aggregate the VAFs of these NSPOPMs by the maximum value. MicroRNA expression analysis shows a strong correlation between miR-31 and maxVAF. Combining maxVAF with miR-31 led to a powerful risk prediction for surgically resected stage I patients (hazard ratio = 8.65, P = 0.001). Our study opens up more options for precision management of stage I LUAD patients.

  Study EGAS00001004461

• A Single-Cell Atlas of the Multicellular Ecosystem of Primary and Metastatic Hepatocellular Carcinoma

  Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generated a single-cell atlas of the multicellular ecosystem of HCCs from four relevant sites. Antitumor central memory T (TCM) cells were found in tertiary lymphoid structures (TLSs). Chronic HBV/HCV infection increases infiltration of CD8+ T cells in tumors but aggravates T cell exhaustion. We identified CD11b+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories contribute to their accumulation. We further demonstrated CD11b+ TAMs promote HCC cells invasion and migration, and angiogenesis. We characterized the heterogeneous subpopulations of malignant hepatocytes and their multifaceted roles in shaping the immune microenvironment. Finally, we identified seven TME subtypes that can predict patient prognosis. Collectively, this large-scale atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating the development of new immune therapy strategies for this malignancy.

  Study EGAS00001004468

• The genomic landscape of lung adenocarcinoma in East Asians

  We performed exome sequencing of 210 and transcriptome sequencing of 181 LUADs of Chinese patients. For more details, please see publication "Genomic landscape of lung adenocarcinoma in East Asians" by Chen J. et. al. in Nature Genetics 2020. https://www.nature.com/articles/s41588-019-0569-6.

  Study EGAS00001002941

• Colorectal adenomas, NKI-AvL TGO series Stool-Proteomics

  Colorectal cancer (CRC) develops from normal epithelium, through a benign precursor lesion called adenoma, by accumulation of genetic alterations affecting oncogenes and tumour suppressor genes. About 5% of colorectal adenomas are estimated to progress to CRC. However, it is important to identify which adenomas actually are at high-risk of progression, because these should serve as intermediate endpoints for e.g. CRC screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high-risk, although this classification lacks solid evidence. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression.For this tissue dataset, we applied low-pass whole genome sequencing to 98 non-advanced and advanced adenomas. These adenomas were classified as lesions with low-risk or high-risk of progression, according to the presence of specific DNA copy number changes (Carvalho et al, CancerPrevRes, 2018).

  Study EGAS00001002953

• Identification of Therapeutic Targets in Rhabdomyosarcoma Through Integrated Genomic, Epigenomic, and Proteomic Analyses

  Personalized cancer therapy based on the somatic mutations identified in patient tumors is becoming an increasingly emphasized approach to improve outcomes of patients with cancer. There are also examples of therapeutic vulnerabilities in cancer that result from changes in gene expression that are a direct or indirect result of tumor specific epigenetic perturbations. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. In this study, we integrated genomic, epigenomic and proteomic data for rhabdomyosarcoma (RMS) to identify therapeutic vulnerabilities. RMS was selected for this analysis because RAS pathway mutations in rhabdomyosarcoma (RMS) are the most common potentially actionable lesions across pediatric solid tumors. The epigenomic data was useful for identifying deregulated developmental pathways in RMS including the WNT, HH, BMP, adenyl cyclase, p38/MAPK and PI3K pathways. Perturbations in those 6 myogenic signal transduction pathways were also evident in the proteome and phosphoteome data. In addition, the proteomic/phosphoproteomic data revealed that the cell cycle checkpoint, unfolded protein response and RB/E2F pathways were deregulated in RMS relative to normal muscle. Recent success targeting CDK4/6 and MEK in adult cancers with RAS mutations led us to test the value of these targets in RMS tumors. We also targeted the unfolded protein response pathway and cell cycle checkpoint pathway using molecular targeted therapeutics in orthotopic patient derived xenografts. Taken together, these data demonstrate the value of integrating epigenomic and proteomic data to identify tumor vulnerabilities that extend beyond somatic mutations identified in the genome.

  Study EGAS00001002967

• Breast implant-associated anaplastic large cell lymphoma shallow whole genome sequencing for copy number analysis and Whole exome sequencing data.

  Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) shallow whole genome sequencing of 29 BIA-ALCL patients for copy number analysis and 24 Alk-negative ALCL samples as control cohort. 7 Whole exome sequencing BIA-ALCL samples.

  Study EGAS00001003962

• Whole-exome sequencing of intravascular large B-Cell lymphoma

  Intravascular large B-cell lymphoma (IVLBCL) is a unique form of diffuse large B-cell lymphoma (DLBCL) characterized by extranodal cell growth especially in small vessels without systemic lymphadenopathy. The limitation in obtaining sufficient tumor materials hampers understanding the molecular pathogenesis of IVLBCL. We performed whole-exome sequencing of IVLBCL using plasma-derived cell-free DNA (cfDNA) and patient-derived xenograft (PDX) samples.

  Study EGAS00001003970

• Spiradenocarcinoma

  • Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. • We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. • H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. • Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy.

  Study EGAS00001001799

• Single cell exome sequencing of lung adenocarcinoma

  Single cell exome sequencing was performed on 200 single cells isolated from a lung adenocarcinoma, female, non-smoker patient. The cells were derived from two distant tumour sectors and a far normal sector. The single cells were amplified on the Fluidigm C1 machine using the GE Healthcare illustra GenomiPhi V2 DNA Amplification Kit prior to sequencing library preparation. In addition, bulk exome sequencing was also conducted for each tumour sectors. For this study, somatic variations were detected from the single cells and phylogenetic clustering was conducted to elucidate the evolutionary trajectory of lung cancer.

  Study EGAS00001002972

• Myeloma WGS

  Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 tumour-normal newly diagnosed pairs and 24 matched relapse tumours from the Myeloma XI trial.

  Study EGAS00001004000

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

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

  Study EGAS00001004001

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

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

  Study EGAS00001002996

• Cell type-specific transcriptomics of esophageal adenocarcinoma as a scalable alternative for single cell transcriptomics

  We developed a protocol for the separation of esophageal carcinoma tissue into leukocytes (using CD45 as a marker), epithelial cells (EpCAM), and fibroblasts (two out of PDGFRA, CD90, anti-fibroblast) by fluorescence-activated cell sorting followed by RNA-sequencing

  Study EGAS00001004053

• Patient-derived neuroblastoma model system OHC-NB1

  Accurate disease modeling presents a bottleneck against effective translation of novel neuroblastoma therapies into the clinic. Recently, considerable intra-tumor genetic heterogeneity has been observed in neuroblastoma, which calls for preclinical models that reflect this feature. Flexibility in a testing platform is also desirable to support assessment of different endpoints and tumor cell characteristics. We present the novel neuroblastoma model OHC-NB1, propagated from a bone marrow metastasis from a patient with INRG stage M, MYCN-amplified neuroblastoma at first diagnosis. To model different aspects of the disease, several preclinical models were developed from the bone marrow aspirate: a tissue plastic-adherent cell line, a 3-dimensional (3D) spheroid culture, and cell line-derived xenografts that were subcutaneously passaged in mice. Typical aspects of MYCN-amplified neuroblastoma, such as MYCN amplification in double minutes, 1p deletion, 17q gain, and a diploid karyotype, are present in OHC-NB1 and persist in all culture types. Whole exome sequencing revealed intra-tumor heterogeneity in the bone marrow metastasis reflected in the culture models. The set of OHC-NB1 cultures with a genetically heterogeneous MYCN-amplified neuroblastoma background provide a flexible preclinical testing system that recapitulates important features of metastatic neuroblastoma.

  Study EGAS00001003031

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126

• Cancer immune control needs senescence induction by Stat1 dependent cell cycle regulator pathways in tumours

  Immune checkpoint bloackade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, we show that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogated both, the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest those cancer cells that escape from eradication.

  Study EGAS00001004151

• 'KOREAN' never-smoker female adenocarcinoma RNA-seq

  Multi-layered genomic studies such as the TCGA project have greatly advanced our understanding on molecular pathogenesis of lung cancer. For Asian nonsmoker patients, however, majority of studies have been limited to mutational analyses, emphasizing ethnic differences in driver mutations (e.g. more frequent EGFR mutations and ALK fusions). In essence, a comprehensive multi-layered characterization that could lead to molecular etiology and patient stratification scheme to be translated into clinical applications for this patient group is still missing. Here we report molecular profiling of tumor and matched normal tissues from 114 non-small-cell lung adenocarcinoma patients using whole exome sequencing, transcriptome sequencing, and array comparative genomic hybridization (CGH).

  Study EGAS00001003789

• Transcriptional changes in GBM through therapy

  Primary glioblastoma (GBM) tumours recur following therapy, owing to treatment resistance mechanisms in unresectable cells. We have sequenced RNA from paired primary and locally recurrent GBM tumours to begin characterising therapy resistant cells and thereby infer the mechanisms by which they evaded treatment. Exome sequencing data from these samples were included in the first data release from the Glioma Longitudinal AnalySiS (GLASS) consortium

  Study EGAS00001003790

• Whole genome sequencing of multiple myeloma identifies novel structural and non-coding mutations.

  The coding region of the myeloma genome is well understood with key mutations having been identified. However, the non-coding regions of the myeloma genome are yet to be analyzed. Here we have performed whole genome sequencing of myeloma patient samples to identify structural abnormalities including chromothripsis and chromoplexy, as well as gene dysregulation through super-enhancer juxtaposition with key oncogenes. We have also identified non-coding region hotspots of mutation, especially in promoter regions, that affect gene expression.

  Study EGAS00001003164

• Integrative molecular analysis of pediatric Anaplastic large cell lymphoma reveals subtypes with distinct immune suppression signatures.

  Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma accounting for 10–15% of all childhood lymphomas. While more than 90% of the ALCL cases contain ALK-rearrangement, these tumors possess significant inter-tumor molecular heterogeneity that contributes to distinct morphologic differences and clinical impact. To gain insight into the molecular heterogeneity within ALK+ ALCL, we performed whole-exome sequencing, RNA-sequencing, and methylome analysis of 42 primary pediatric ALK+ ALCL patients. Our data showed that ALK+ALCLs was subclassified into two subtypes based on ALK gene expression, methylation profiles, and somatic mutation patterns. ALK-low samples had more highly methylated gene regions while enriched with immune infiltration. ALK-high samples were enriched with somatic copy number alteration and high expression of MYC and PD-L1. These data indicate that ALK expression, somatic mutations, and aneuploidy status are negatively associated with immune infiltration, stipulating that ALK expression status might be associated with resistance to immune checkpoint inhibitors.

  Study EGAS00001004189

• Analysis of exonic somatic variants in light-chain amyloidosis (ALA) and ALA concomitant with multiple myeloma

  We aim to provide the very first insight into ALA+MM molecular profiles and compare the results with ALA and with MM. Our detailed study of ALA and ALA+MM represents an important step towards improved understanding of their genetic and transcriptomic background, which is a prerequisite for development of optimal treatment strategies in the future.

  Study EGAS00001004214

• Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

  High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.

  Study EGAS00001004235

• Whole-exome sequencing of ovarian clear cell carcinoma in clinical outliers

  Whole-exome sequencing dataset for the Australian Ovarian Cancer Study (AOCS) and The Jikei University School of Medicine (JIKEI) ovarian clear cell carcinoma (OCCC) clinical outliers project, representing 10 donors. Although OCCC are commonly resistant to platinum based chemotherapy, good clinical outcomes are observed in a subset of patients. Exome sequencing was performed in 10 patients who had either unusually long survival (N=5) or had a very short time to progression (N=5).

  Study EGAS00001004248

• Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

  Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies (ONT) PromethION platform is a now a viable solution for WGS. New bioinformatic methods have been developed to take advantage of this long read data, however much of the validation of these tools has focussed on calling germline variants (both SNVs and structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated due to their frequency varying depending on tumour purity/subclonality. Here, we evaluate the extent to which Nanopore WGS enables genome-wide detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma. We examine the capability of currently available tools for calling somatic variants in ONT data by comparing the data with results from 150bp short-read sequencing of the same samples. We then conduct a detailed analysis of the performance of multiple long-read mappers and structural variant callers for calling large, somatic structural variants (SVs) in ONT data. Our protocol achieved yields of up to 96 mapped Gb per PromethION flow cell with average read lengths of ~5kb. Calling germline SNVs from these data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialized joint calling algorithms. Our analysis of structural variants shows that the comparative performance of different tools varies significantly between SV types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants by using the ONT data to confirm that a somatic 1.6Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

  Study EGAS00001004266

• Multiplexed quantification of four neuroblastoma DNA targets in a single droplet digital PCR reaction

  Evaluation of quadruplex ddPCR-based copy number assessment in blood plasma samples paired with genomic DNA from the corresponding primary neuroblastoma from three patients and comparison with copy numbers determined by duplex and triplex ddPCR and re-analyzed from whole-exome sequencing (WES) data.

  Study EGAS00001004275

• Analysis of IDHwt-glioblastoma samples from paired primary and recurrent tumor samples

  IDHwt-glioblastomas rapidly recur after initial treatment. To study genetic evolution in glioblastoma, we analyzed whole genomes of 21 pairs of primary and recurrent tumor samples using next generation sequencing. In addition we sequenced RNA from 16 tumor pairs and a panel of 50 glioma-associated genes in tumor pairs from 43 patients (including 14 of the 21 patients included in the WGS discovery set). Glioblastoma subtypes were determined using 450k/EPIC methylation arrays. This study was supported within the e:med program of the German Ministry of Education and Research (BMBF) by the collaborative research project ‘SYS-GLIO - Systems-based prediction of the biological and clinical behavior of gliomas’ (https://www.sys-med.de/de/demonstratoren/sys-glio/) This study is part of the Heidelberg Center for Personalized Oncology - HIPO-043

  Study EGAS00001003184

• Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

  Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent non-coding mutations surrounding a single exon of the HNRNPH1 gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent non-coding mutations in disrupting an auto-regulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly implicate a role for aberrant regulation of mRNA processing in MCL pathobiology.

  Study EGAS00001004289

• The Landscape of Genetic Alterations in Hepatocellular Carcinoma, 88 matched HCC tumour/normal pairs WGS belongs to ICGC LICA-CN project

  Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy. Whole genome shotgun sequencing (WGS) and the landscaple of somatic mutations in 88 paired samples from HCC patients including tumors and matched adjacent normal tissues using Illumina HiSeq 2000 platform were performed.

  Study EGAS00001002218

• Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma (arrays set)

  Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood of virtually all MM cases and are prognostic, but their applicability for non-invasive screening has been poorly investigated. Here, we used next-generation flow cytometry to isolate matched CTCs and BM tumor cells from 42 patients and compare their genetic profile. In 8 cases, tumor cells from extramedullary plasmacytomas were also sorted and whole-exome sequencing performed in the three spatially-distributed clones. Noteworthy, ≥84% mutations present in BM and extramedullary clones were detectable in CTCs. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy-number alterations (≥94%) though not for translocations (43%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Altogether, these results support CTCs for non-invasive risk-stratification of MM patients based on their numbers and genetic profile.

  Study EGAS00001004314

• Comprehensive molecular characterization of brainstem glioma

  Brainstem gliomas are the most devastating and lethal tumors. Survival rates are among the lowest in all cancers and options for intervention are likewise low. Due to anatomical delicacy of these areas, resection of tumors is particularly difficult and attempted resections have high perioperative mortality rates. Genomic and epigenetic studies often provide a gateway to functional studies of specific classifications of tumors that can lead to major breakthroughs in diagnosis and treatment options.

  Study EGAS00001004341

• Enhanced reduced representation bisulfite sequencing (eRRBS) on 45 multiple myeloma samples and 3 normal plasma cell

  Enhanced reduced representation bisulfite sequencing (eRRBS) on 45 multiple myeloma samples and 3 normal plasma cell. Libraries were sequenced on a HiSeqTM4000 Illumina machine using 75bp paired-end reads

  Study EGAS00001004348

• Control samples, breast cancer clinical samples and matched patient-derived tumour xenografts (PDTXs) to develop and test a computational approach to discriminate human and mouse sequences in PDTXs

  Patient-Derived Tumour Xenografts (PDTXs) have emerged as the pre-clinical models that best represent clinical tumour diversity and intra-tumour heterogeneity. The molecular characterization of PDTXs using High-Throughput Sequencing (HTS) is essential; however, the presence of mouse stroma is challenging for HTS data analysis. Indeed, the high homology between the two genomes results in a proportion of mouse reads being mapped as human. In this study we generated Whole Exome Sequencing (WES) and RNA sequencing (RNA-seq) data from samples with known mixtures of mouse and human DNA or RNA.

  Study EGAS00001002445

• Genetic Risk for Subsequent Neoplasms among Long-term Survivors of Childhood Cancer in the St. Jude Lifetime Cohort

  While childhood cancer survivors are known to be at increased risk of subsequent neoplasms (SNs), the contribution of germline mutations in cancer predisposition genes to the risk of SN is largely unknown. Whole-genome sequencing (30X) was performed on 3,006 5+ year survivors of childhood cancer (median age, 35.8 [range: 7.1-69.8] years) from the St. Jude Lifetime Cohort. Survivors underwent a comprehensive clinical assessment. Germline mutations in 156 cancer predisposition genes (SJCPG156), including a subset of 60 (SJCPG60) autosomal dominant genes with moderate to high penetrance, were classified for their pathogenicity. Piecewise exponential regression, stratified by radiation exposure, was used to evaluate the relative rate (RR) and 95% confidence interval (95% CI) of SN occurrence by mutation status. Pathogenic or likely pathogenic mutations in SJCPG156 and SJCPG60 were identified in 11.7% and 5.8% of survivors, respectively. The most frequently mutated SJCPG60 genes included RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12) and TP53 (n=10). Mutations in SJCPG60 were associated with the rate of subsequent sarcoma (RR, 10.3; 95% CI, 4.2 to 25.6) and breast cancer (RR, 13.3; 95% CI, 5.8 to 30.5) among irradiated survivors, and the rate of developing any SN (RR, 4.8; 95% CI, 2.4 to 9.4) and breast cancer (RR, 7.8; 95% CI, 2.5 to 24.0) among non-irradiated survivors. The rate of developing ≥2 histologically distinct SNs was increased 17.8-fold (95% CI, 3.5 to 89.8) among SJCPG60 mutation carriers treated without radiotherapy. Similar but attenuated associations were observed for mutations in SJCPG156. Survivors who develop a SN without prior radiotherapy or who are diagnosed with a subsequent sarcoma or breast cancer within a site of prior radiotherapy should be referred to genetic counseling.

  Study EGAS00001002499

• Hepatoblastoma tumoroid biobank as a key resource for tumour genetics

  Study EGAS00001008251

• Combined clinical and gene expression score identifies high-risk individuals among follicular lymphoma patients on immunotherapy

  Follicular lymphoma (FL) is usually an indolent malignant B-cell lymphoma, but at least 30% of the patients experience transformation to Diffuse Large B-cell Lymphoma (DLBCL) with inferior survival. Early identification of patients with poor prognosis is essential for tailoring treatment. Here, we describe a network-based integrative analysis of 168 FL-biopsies from 127 patients with long clinical follow-up and transformation status. A distinct shift in expression towards a DLBCL expression phenotype is observed in BTK associated genes in cases with transformation. This shift is present years prior to transformation. An integrated score combining the BTK score and a clinical index is proposed, termed the BTK-FLIPI score. It identifies patients (16%) with very poor prognosis, with median time to progression 21.7 months (95% CI: 14.3-42.6) versus 70.9 months (95% CI: 41.5-95.0) for the remainder. The results suggest BTK as a potential target for treatment of high-risk FL-patients.

  Study EGAS00001002566

• Reduced Representation Bisulfite Sequencing (RRBS) in various tissues to discover DNA methylation markers for the diagnosis of breast and ovarian cancer.

  Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. In addition, monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence.In order to discover the most relevant CpG regions, we used RRBS and analysed several tissue samples: 11 prospectively collected invasive epithelial ovarian cancer samples (high grade serous n=8, low grade serous n=1, endometrioid n=1, mucinous n=1, mean age = 54.7 years), 8 prospectively collected invasive ductal breast cancer samples (2/8 triple negative; mean age = 56.6 years), one benign tumor (papillary serous cystadenoma, age = 86 years), 18 non-neoplastic tissue samples (breast n=7 and adnexal n=11, mean age = 60.2 years), two non-neoplastic endometrial tissues (mean age = 68 years) and twenty three white blood cell samples (mean age = 57.8 years) were assessed by RRBS. Genome wide methylation analysis was performed by Reduced Representation Bisulfite Sequencing (RRBS) at GATC Biotech. DNA was digested with MspI followed by size selection of the library, providing enhanced coverage for the CpG-rich regions. The digested DNA was adapter ligated, bisulfite modified and PCR amplified. The libraries were sequenced on Illumina’s HiSeq 2500. Analysis of the first samples sequenced with 100bp paired-end mode showed that the library insert size was small. Therefore, the remaining samples were sequenced with 50 bp paired-end mode. Using Genedata Expressionist® for Genomic Profiling v9.1, we established a bioinformatics pipeline for the detection of cancer specific differentially methylated regions (DMRs). The most promising DMRs were taken forward for the development and validation of serum based clinical assays.

  Study EGAS00001002609

• Sequencing of an adolescent patient with germline RET mutant alveolar rhabdomyosarcoma

  An adolescent patient presented with an alveolar rhabdomyosarcoma made more unique by the presence of a germline RET mutation ordinarily associated with and a known driver of multiple endocrine neoplasia type 2A (MEN2A) cancer. To better understand the role of this germline RET mutation in the genetics and phenotypic response of this unique alveolar rhabdomyosarcoma, we performed DNA and RNA sequencing of the patients in addition to functional studies on patient-derived cultures and genetically similar similar cell models.

  Study EGAS00001004359

• Gene expression profiling of nasopharyngeal carcinoma

  We retrospectively collected 150 non-metastatic, pretreatment, formalin-fixed, paraffin-embedded (FFPE) nasopharyngeal carcinoma (NPC) samples as validation cohort 1. Also, we prospectively collected 32 FFPE samples from NPC patients enrolled in a trial evaluating anti-PD-1 antibody as validation cohort 2. Total RNA was extracted and hybridised to an Affymetrix HTA 2.0 microarray. In this study, we investigated the immune status of the tumour microenvironment (TME) based on gene expression profiles to classify NPC into biologically distinct immune subtypes, and clarify their associations with prognosis and immunotherapy response.

  Study EGAS00001004542

• Comprehensive Genomic Characterization of Refractory Multiple Myeloma Reveals a Complex Mutational and Structural Landscape Associated with Drug Resistance (H067)

  Outcome of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is still very poor. To elucidate the genetic landscape of relapsed/refractory MM (RRMM) we performed whole genome and transcriptome sequencing of 39 heavily pretreated RRMM patients with at least double refractoriness revealing complex structural changes and a high mutational load (H067/K08K). We found a median of 67 structural variants and 116 nonsynonymous exonic mutations per patient. Assessment of oncogenic drivers showed NRAS, BRAF, TP53, KRAS, SLC4A7, FAM46C, DIS3, RB1, KMT2C, MLLT4, EWSR1, HCFC2, and COPS3 as significantly mutated. We found multiple genomic regions with bi-allelic events affecting known tumor suppressor genes, most frequently TP53, RB1, and TRAF3. Supervised analysis of mutational signatures showed a major contribution of Cosmic signature 6 associated with deficiency in DNA mismatch repair and the ‘BRCAness’ signature which coincided with mutations in genes known to confer PARP inhibitor sensitivity. Recurrently mutated gene networks included genes with relevance for PI and IMiD activity, the latter including in particular members of the Cereblon and the COP9 signalosome complex. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.

  Study EGAS00001004363

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

  Endometrioid ovarian carcinoma (EnOC) is an under-investigated type of ovarian carcinoma. Here, we report the largest genomic study of EnOCs to date, performing whole exome sequencing of 112 cases following rigorous pathological assessment. High frequencies of mutation were detected in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a novel target of recurrent mutation in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy was constructed using a novel algorithm (PRISTINE), identifying clinically distinct EnOC subtypes: TP53m cases demonstrated greater genomic complexity, were frequently FIGO stage III/IV at diagnosis (48%) and incompletely debulked (44%), and demonstrated inferior survival; conversely, CTNNB1m cases demonstrated low complexity and excellent clinical outcome, were predominantly stage I/II at diagnosis (89%) and completely resected (87%). Tumour complexity provides further resolution within the TP53wt/CTNNB1wt group. Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

  Study EGAS00001004366

• Cerebrospinal fluid circulating tumour DNA allows the characterisation and monitoring of medulloblastoma

  The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. In this study we show that CSF ctDNA allows the molecular characterisation and monitoring of medulloblastoma. This can ultimately facilitate the clinical management of medulloblastoma patients.

  Study EGAS00001004651

• Multiple Myeloma Total Therapy trial patient sequencing

  The study of multiple myeloma (MM) genomics has identified many abnormalities that are associated with poor progression free survival (PFS) and overall survival (OS). Copy number abnormalities have been extensively studied in many datasets with long follow-up, however, the prognostic impact of mutations have not been extensively studied and available datasets have generally had a relatively short follow-up. These analyses have identified a range of mutations that are associated with prognosis, making it important to extend these observations in larger studies with robust diagnostic technologies. Samples from newly diagnosed MM patients enrolled in Total Therapy trials (n=225) were sequenced on a targeted panel consisting of 140 genes and additional regions of interest for copy number, as well as tiling of the Ig and MYC loci for detection of translocations. Samples were sequenced to a median depth of 452x using 2x75 bp paired end reads. Reads were aligned to hg19 and mutations called using Strelka and filtered with fpfilter. Translocations were called by Manta, and copy number determined by read depth ratio and loss of heterozygosity comparison with a patient matched non-tumor sample. DNA was obtained from either CD138+ cells from the bone marrow of multiple myeloma patients (tumor) or from stem cell harvests or peripheral blood cells from the same patient (control). 100 ng of DNA was fragmented, end-repaired, and adapters ligated using the HyperPlus kit (KAPA Biosystems). After PCR amplification the libraries were hybridized with probes against either a targeted panel consisting of 140 genes and chromosomal regions (Nimblegen) using SeqCap reagents (Nimblegen). Hybridized libraries underwent further amplification before being sequenced on a NextSeq500 (Illumina) using 75 bp paired end reads There are 450 (225 tumor and 225 germline) samples in this study. 263 are available as part of this dataset. The remaining 187 are available with dataset accession id EGAD00001004117.

  Study EGAS00001003223

• Neuroblastoma and adrenal gland single-cell study

  Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. However, the cellular origin of neuroblastoma remains to be defined. Here, we study single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development. We define normal differentiation trajectories during adrenal medullary development and identify the cellular origin of neuroblastoma. Importantly, adrenergic and mesenchymal neuroblastomas with varying clinical phenotypes match different temporal states along normal differentiation trajectories, with the degree of differentiation corresponding to clinical prognosis.

  Study EGAS00001004388

• Fibroblast heterogeneity drives metastatic spread in breast cancer through distinct mechanisms

  The major cause of death among breast cancer patients is metastatic dissemination, suggesting that understanding the mechanisms driving this process remains an unmet medical need. Here, by concomitantly using 5 markers, we identify 4 Carcinoma-Associated Fibroblasts (CAF) subsets in primary tumors and corresponding metastatic lymph nodes (LN). Two CAF subsets, called CAF-S1 and CAF-S4, correlate with the proportion of cancer cells in invaded LN and exert distinct functions in tumor cell spread. CAF-S1 promote cancer cell migration and initiates an epithelial to mesenchymal transition through a CXCL12 / TGFb positive loop. For their part, the highly contractile CAF-S4 foster cancer cell motility and invasion in 3-dimensional matrix via Notch pathway activation. Finally, CAF-S1 and CAF-S4 accumulation in LN is a new prognostic factor at diagnostic, independent of breast cancer subtypes and LN status, strengthening the validity of our findings in human breast cancer pathophysiology.

  Study EGAS00001003238