4115 results for "*oma"

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• Growth Hormone (GH) -secreting Pituitary Adenoma

  We profiled the somatic landscape of 21 growth hormone (GH) -secreting pituitary adenomas using somatic copy-number alteration (SCNA), whole-genome sequencing (WGS), bisulfate sequencing, and transcriptome approaches. See details in Valimaki et al. Genetic and epigenetic characterization of growth hormone (GH) - secreting pituitary tumors. Manuscript in preparation, 2019.

  Study EGAS00001003488

• Predicting brain tumor recurrence: development and validation of a DNA-methylation based nomogram in meningioma

  Our work is the first to demonstrate the transformative utility of integrating clinical and molecular factors for use beyond simple classification into the realm of individualized prognostication for any brain tumor. Using our developed and validated tools that are publicly available, clinicians will be able combine clinical and molecular factors to determine an individualized probability of recurrence for patients with meningiomas. This represents a major advance in the field of personalized medicine for neuro-oncology, and the use of this tool can help clinicians overcome one of the most challenging limitations we face when treating patients with meningiomas.

  Study EGAS00001003490

• 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

• 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

• 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

• 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

• Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma

  Background: Cancer patients with advanced disease exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates sequencing data with functional assay data to develop patient-specific combination cancer treatments. Methods: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient’s epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient’s primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. Results Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). Conclusions These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.

  Study EGAS00001003564

• Sequencing data of multiple sarcoma samples for personalized medicine and endotype identification

  Sequencing data derived from multiple patient samples was used to guide multiple patient-specific experiments and identify potential therapeutic options. These diseases are rare and high-risk (undifferentiated pleomorphic sarcoma, rhabdomyosarcoma) and thus have few available validated clinical options. This leaves the population of patients with few options if, and when, standard therapy fails to cure or control disease. An aspect of the personalize therapy design included the identification of broader disease endotypes (a combination of genetic and clinical data describing patient status) to identify subgroups of the individual disease that could better define treatments and could segment patient populations for deeper preclinical research.

  Study EGAS00001003981

• Multi-region exome sequencing of lung adenocarcinoma precursors -1

  To characterize the genomic landscape of invasive lung adenocarcinoma and its precursors; to depict the genomic evolution from preneoplasia of lung to invasive lung adenocarcinoma; to decipher mechanism to drive the tumor progression.

  Study EGAS00001003439

• RNA-sequencing of adult T-cell leukemia/lymphoma samples

  Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. In this study, we performed RNA-sequencing (RNA-seq) analysis for ATL samples including 9 primary tumors and 1 ATL cell line to clarify gene expression profiles in this disease.

  Study EGAS00001003575

• A Phase II Trial of High Dose Interleukin-2 and Multi-site Stereotactic Ablative Radiotherapy for Patients with Metastatic Renal Cell Carcinoma

  Immune-based therapies have improved outcomes for metastatic renal cell carcinoma (mRCC) but there is still a significant margin for improvement. Here, we report the results of a phase II trial combining high dose Interleukin-2 (HD-IL-2) with stereotactic ablative body radiotherapy (SAbR) for patients with metastatic renal cell carcinoma.

  Study EGAS00001003605

• Recapitulation of genetic predisposition to medulloblastoma in human neuroepithelial stem cells

  Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome, patients predisposed to medulloblastoma due to germline mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

  Study EGAS00001003620

• Berlin Neuroblastoma Dataset DAC

  Dac EGAC00001003082

• Berlin Neuroblastoma Dataset DAC

  Dac EGAC00001003112

• Analysis of copy number variation landscape of glioma by shallow coverage whole genome sequencing

  We reported shallow coverage whole genome sequencing (WGS) is an economic method for identification of whole genome somatic copy number variation (SCNV). Combining with a Taqman low density array (TLDA) designed for molecular subtyping of glioma, it enabled classification of glioma into biological entities with different cellular origin and genomic alterations. Further, we also showed shallow-coverage WGS enabled systematic identification of clonal and subclonal SCNV in glioma genomes and the burden and pattern of SCNV can serve as an objective marker of tumor progression and predict risk and relapse.

  Study EGAS00001003690

• ID1 in glioblastoma

  Study EGAS00001003711

• Infant Glioma Molecular Subtype

  Infant gliomas have completely different clinical behavior than gliomas in children and adults. Low-grade tumors are more aggressive with a higher mortality rate, while high-grade tumors are more benign. However, we have little understanding of their biology and so cannot explain this behavior and what constitutes optimal clinical management. To solve this enigma, we performed a comprehensive genetic analysis of the largest cohort to date of infantile gliomas. We uncovered several important findings which dramatically change the management of these cancers. Infant hemispheric gliomas harbor unique alterations in ROS, ALK, MET and other genes found in adult carcinomas. Unlike in adults, they are typically the only alteration present and some of these tumors regress from high- to low-grade partially explaining their favorable clinical outcome. Midline gliomas harbor RAS/MAPK pathway mutations, progress rapidly, and do not respond to current chemoradiation approaches, partially explaining their poorer outcome. These data suggest that infant gliomas require different therapeutic approaches including early use of targeted therapies.

  Study EGAS00001003714

• Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma

  TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier in this setting is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort (n=95) and determined their impact on survival.

  Study EGAS00001005617

• Analysis of the genomic landscape of chemoresistant multiple myeloma

  Study EGAS00001003709

• Cancer and germline exomes consisting of FASTQ paired-end reads from melanoma and lung cancer samples

  Efforts to precisely identify tumor human leukocyte antigen presented peptides (HLAp) capable of mediating T cell based tumor rejection still face important challenges. Recent reports suggest that non-canonical cancer HLAp could be immunogenic but their identification requires highly sensitive and accurate mass-spectrometry (MS)-based proteogenomics approaches. Here, we present a MS-based analytical pipeline that can precisely characterize the non-canonical HLAp repertoire, incorporating whole exome sequencing, bulk and single cell transcriptomics, ribosome profiling, and a combination of two MS/MS search tools. This approach results in the accurate identification of hundreds of shared and tumor-specific non-canonical HLAp. Albeit often at low levels and in distinct subpopulations of cells, numerous non-canonical HLAp are shared across tumors. This analytical platform holds great promise for the discovery of novel cancer antigens for cancer immunotherapy.

  Study EGAS00001003723

• DNA Methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load

  Mitotic cell division increases tumour mutation burden and copy number load with a positive and inverse correlation, respectively, with the clinical benefit of immunotherapy. Markers of cell division correlate also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation as a combination regimens for precision immunotherapy.

  Study EGAS00001003731

• Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

  Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DDR genes. Upon knockdown of histone demethylases KDM4C and KDM7A both differentiation and DNA damage was induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

  Study EGAS00001003750

• Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes

  We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes.

  Study EGAS00001003093

• Polyomavirus-positive Merkel cell carcinoma derived from a trichoblastoma suggests an epithelial origin of Merkel cell carcinoma

  Study EGAS00001003784

• Methylation 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 EGAS00001003800

• Genetic modification of primary human B cells to model high-grade lymphoma

  Study EGAS00001003560

• Whole genome and whole transcriptome sequencing of Hepatosplenic T Cell Lymphoma tumor.

  Whole genome and whole transcriptome sequencing of Hepatosplenic T Cell Lymphoma tumor.

  Study EGAS00001003775

• 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

• RNA 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 EGAS00001003841

• 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 genome and whole transcriptome sequencing of patients diagnosed with angiosarcoma.

  Angiosarcomas are rare, clinically-aggressive tumors with a predilection for the elderly and immunosuppressed, which has incited suspicion of an oncogenic virus. We studied the metagenomic landscape of angiosarcomas and identified reads mapping to human herpesvirus-7 (HHV-7). Overall, HHV-7 was present in two-thirds of angiosarcomas, particularly in cases with low tumor mutation burden and lacking signatures of ultraviolet-induced DNA damage. Transcriptomic profiling revealed the enrichment of tumor inflammation signatures in HHV7-positive angiosarcomas. In conclusion, we identified a distinct “inflammatory” subtype of angiosarcoma associated with HHV-7.

  Study EGAS00001003895

• Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform

  Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell Carcinoma (ccRCC) with percutaneous biopsies and is a confounding factor in selection of molecular-targeted versus immune-based therapy. Magnetic Resonance (MR) Imaging can noninvasively assess the spatial landscape of the entire tumor. To validate MRI for ITH assessment, we implemented a radiogenomic platform through a systematic imaging based co-localization approach for multi region tissue acquisition from single tumors. We investigated if the spatial changes in imaging can predict the molecular changes using transcriptome and histopathological correlatives. Our study confirmed imaging heterogeneity as a predictor of molecular heterogeneity in ccRCC.

  Study EGAS00001003846

• Whole Genome Sequencing Reveals Potential Therapeutic Strategy for Monomorphic Epitheliotropic Intestinal T-cell Lymphoma

  Whole Genome Sequencing Reveals Potential Therapeutic Strategy for Monomorphic Epitheliotropic Intestinal T-cell Lymphoma

  Study EGAS00001003876

• Immuno-genomic landscape of osteosarcoma

  Osteosarcoma is an orphan disease affecting children and young adults that has seen little to no progress in survival outcomes for >30 years. Despite having heavily rearranged genomes, to date, clinical trials with immunotherapy have shown no benefit for patients with osteosarcoma. In this study, we conducted the first multi-platform immune profiling (whole genome, transcriptome, T-cell receptor sequencing, immunohistochemistry and reverse phase protein array) on every available pediatric and adult osteosarcoma patients from our institution (N = 48) with the goal of describing immune features that may contribute to immunotherapy resistance.

  Study EGAS00001003887

• Immuno-genomic landscape of osteosarcoma

  Osteosarcoma is an orphan disease affecting children and young adults that has seen little to no progress in survival outcomes for >30 years. Despite having heavily rearranged genomes, to date, clinical trials with immunotherapy have shown no benefit for patients with osteosarcoma. In this study, we conducted the first multi-platform immune profiling (whole genome, transcriptome, T-cell receptor sequencing, immunohistochemistry and reverse phase protein array) on every available pediatric and adult osteosarcoma patients from our institution (N = 48) with the goal of describing immune features that may contribute to immunotherapy resistance.

  Study EGAS00001004197

• Characterizing the immune and genome landscapes for osteosarcoma

  Osteosarcoma have heavily rearranged genomes and moderate tumor mutation burden, which suggests that the patients may express neoantigens that could be targeted by immune cells. To characterize the immunogenomic landscape of this disease, we performed genome, transcriptome, immune and proteomic profiling of 48 patients comprised largely of relapsed and metastatic cases from both pediatric and adult patients.

  Study EGAS00001003247

• WES of 2 human osteosarcoma and corresponding cell lines

  Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.

  Study EGAS00001003923

• 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

• Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

  Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAEs) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the break-down of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Tregs) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+CD25+CD127– Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings propose an inflammatory Treg reprogramming as a feature of immunotherapy-induced irAEs, that may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.

  Study EGAS00001004694

• SCC ctDNA sequencing

  In this study we have sequenced the ctDNA of 28 Squamous Cell Carcinoma patients in the TP53 gene, each sample has been sequenced twice.

  Study EGAS00001003987

• SCC tumor sequencing

  In this study we have sequenced the tumor of 28 Squamous Cell Carcinoma patients.

  Study EGAS00001003988

• Uncovering tumor intrinsic and extrinsic factors that regulate hepatocellular carcinoma growth using patient derived xenograft assays

  Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, human HCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient derived xenograft (PDX) models. In Asia, HCCs from hepatitis B virus patients have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NSG mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passageability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the US. PDX models preserved the histology and genetic features of parental tumors, and ultimately, 9 new models were usable for pre-clinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib and CCA PDXs were also highly sensitive to regorafenib. PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the US.

  Study EGAS00001004020

• Myeloma RNAseq

  Study EGAS00001003999

• UCSF Pediatric Bithalamic Glioma Genome Project

  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. We performed targeted next-generation sequencing of approximately 500 cancer-associated genes on a cohort of 13 pediatric bithalamic diffuse gliomas, a lethal brain tumor of childhood for which the genetic basis is largely unknown. We identified that bithalamic diffuse gliomas harbor frequent mutations in the EGFR oncogene in the absence of accompanying gene amplification and only rare histone H3 mutation. These EGFR mutations were either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain). Accompanying alterations included frequent TP53 mutation, CDK6 amplification or CDKN2C mutation, and BCOR and BCORL1 mutation or deletion.

  Study EGAS00001004033

• 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

• Neoadjuvant combination PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable urothelial carcinoma

  Immune checkpoint therapy (ICT) is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma (UC), with one study reporting data in cisplatin-ineligible patients who received anti PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathologic complete response (pCR) rate of 17%. Here, we report on the first pilot combination neoadjuvant trial (NCT02812420) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high risk features (N=28). Primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (N=4), hepatitis and colitis (N=2). We also observed pCR of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (N=24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized UC, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Publication: Gao et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nature Medicine volume 26, pages1845–1851(2020)

  Study EGAS00001004074

• Molecular and Clonal Evolution in Recurrent Metastatic Gliosarcoma

  We present a rare case of a 37-year-old woman who was initially diagnosed with IDH wild-type gliosarcoma in the frontal lobe and later developed two local recurrences and extracranial metastases to the vertebral and pelvic bones. In order to understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. Mutational and copy number profile comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile, but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.

  Study EGAS00001004076

• Exon4-mutations in KRAS Affect MEK-ERK and Pi3K-AKT Signaling in Multiple Myeloma

  Approximately 40% of MM cases harbor a point mutation in either KRAS or NRAS. However, it is still unclear whether RAS-mutations are associated with disease outcome. Specifically, no information exists whether KRAS-mutations have an impact on survival in MM patients at diagnosis that were treated with novel agents (e.g. bortezomib, lenalidomide). Targeting KRAS directly for therapeutic purposes is still impossible, but recently the first covalent mutant-specific inhibitor targeting KRASG12C made it into clinical trials. However, other KRAS-hotspot-mutations exist in MM patients, including the less common exon4-mutations. Within the current study, the coding regions of KRAS in 80 MM patients at diagnosis, uniformly treated with bortezomib and high-dose chemotherapy, were deep-sequenced. Moreover, the functional impact of KRASG12A as well as the two exon4-mutations A146T (AMO1) and A146V (MM patient) on different survival pathways was investigated. Specifically, an siRNA-mediated knockdown in AMO1 was performed and KRASWT, KRASG12A, KRAS146T and KRAS146V were overexpressed in the KRASWT cell lines JJN3 and OPM2 using lentiviral transduction and the transposase based Sleeping Beauty system. KRAS-mutations were not associated with survival. Yet, the expression of all KRAS-mutants had an impact on MEK/ERK-signaling in two independent MM cell lines and on AKT/PI3K-signaling in one MM cell line.

  Study EGAS00001004110

• Phased whole genome sequencing of 10 melanoma samples

  We have sequenced 10 melanoma samples using 10X linked reads technology to obtain phased whole genome sequence data. Using this data, we created diploid personalized genomes for each sample and aligned functional genomics data obtained from the same samples in order to find allele specific events (such as allele-specific binding and allele-specific chromatin accessibility).

  Study EGAS00001004136