4116 results for "*oma"

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• Bulk RNAseq dataset for "Longitudinal Multi-Omics Study Reveals Molecular Drivers and Tumor Microenvironment in Extramedullary Multiple Myeloma"

  This dataset contains 84 paired fastq files of Bulk RNAseq collected from 14 patients with Extramedullary multiple myeloma, 14 patients with newly diagnosed multiple myeloma and 14 patients with Relapsed/refractory multiple myeloma

  Dataset EGAD50000000051

• WES dataset used for the study "Longitudinal Multi-Omics Study Reveals Molecular Drivers and Tumor Microenvironment in Extramedullary Multiple Myeloma"

  This dataset contains 72 paired fastq files of raw Whole exome sequencing data from 14 patients with Extramedullary myeloma, 8 paired samples from the same patients at the time of Newly diagnosed myeloma, and the corresponding normal samples

  Dataset EGAD50000000052

• singel cell RNAseq dataset for the study "Longitudinal Multi-Omics Study Reveals Molecular Drivers and Tumor Microenvironment in Extramedullary Multiple Myeloma"

  This dataset contains 16 fastq files of raw single-cell RNAsequencing data from 6 patients with Extramedullary multiple myeloma used for the study "Longitudinal Multi-Omics Study Reveals Molecular Drivers and Tumor Microenvironment in Extramedullary Multiple Myeloma"

  Dataset EGAD50000000053

• DAC Longitudinal Multi-Omics Study Reveals Molecular Drivers and Tumor Microenvironment in Extramedullary Multiple Myeloma

  Data access requests for the raw data used in publication "Longitudinal Multi-Omics Study Reveals Molecular Drivers and Tumor Microenvironment in Extramedullary Multiple Myeloma"

  Dac EGAC50000000016

• Healthy_pleura

  EPIC methylation data of pleural mesothelioma samples and healthy pleura samples

  Dataset EGAD00010002656

• Pleural_mesothelioma

  EPIC methylation data of pleural mesothelioma samples and healthy pleura samples

  Dataset EGAD00010002657

• Activation of Wnt/β-catenin signalling by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary gland basal cell adenoma - WES

  Wnt signalling must be 'just right' to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genomic profiles of BCA and BCAC have not been explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-functon (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to β-catenin and the accumulation of β-catenin in cells. This was consistent with the nuclear expression of β-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/β-catenin pathway and defines a novel mechanism of Wnt pathway control. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-κB signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

  Dataset EGAD00001015365

• Activation of Wnt/β-catenin signalling by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary gland basal cell adenoma - RNA

  Wnt signalling must be 'just right' to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genomic profiles of BCA and BCAC have not been explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-functon (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to β-catenin and the accumulation of β-catenin in cells. This was consistent with the nuclear expression of β-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/β-catenin pathway and defines a novel mechanism of Wnt pathway control. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-κB signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

  Dataset EGAD00001015366

• Single cell transcriptomic profiles of advanced melanoma patients treated with checkpoint inhibitor immunotherapy

  Little is known about the resistant clones within the tumour ecosystem treated with immunotherapy. This work provides a comprehensive and integrative analysis of each individual non-responding melanoma patients, including clinical features integrated with single cell analysis, which is critical to understand features of resistance in order to improve cancer patients’ outcomes.

  Study EGAS50000000339

• Single cell RNA sequencing data of advanced melanoma patients treated with checkpoint inhibitor immunotherapy

  Single cell RNA libraries were prepared using 10x Genomics Chromium Next GEM Single Cell 3’ v2 reagents. The samples were barcoded and each library were pooled with two samples at equimolar concentrations. The pooled libraries (n=4) were sequenced on the NextSeq 500 machine (Illumina) with paired-end sequencing and dual indexing as recommended in the manufacturer’s protocol; 26 and 98 cycles for the respective Read 1 and 2, and 8 cycles for i7 index.

  Dataset EGAD50000000493

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

  Study EGAS00001004288

• Multiregional non-invasive genetic characterization of MM

  Genomic characterization (through whole-exome sequencing) of circulating tumor cells, bone marrow clonal plasma cells and extramedullary plasmacytomas from multiple myeloma patients.

  Dataset EGAD00001006028

• Tracking the evolution of Therapy-Related Myeloid Neoplasms using chemotherapy signatures

  Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient’s life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes chemotherapy exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.

  Study EGAS00001006903

• Genomic profiles associated with response to immunotherapy in adolescent and young adult patients with melanoma

  The patterns of immune infiltration and treatment responses are unclear due to genomic and clinicopathological differences in AYA patients compared to those of older patients, and these patterns and differences may contribute to the lack of response to immunotherapy. This study fills the research gaps in understanding the molecular profiles of AYA melanoma and the key immunosuppressive signalling pathways contributing to tumour growth and resistance to immunotherapy

  Study EGAS50000000238

• RNAseq from a study of MYC, BCL2 and BCL6 rearrangements in non-Hodgkin lymphoma.

  Paired-end ribodepletion RNAseq performed on 257 samples of Burkitt lymphoma, diffuse large B cell lymphoma, follicular lymphoma, and high-grade B cell lymphoma with MYC and BCL2 or BCL6 rearrangements. RNA was derived from either fresh frozen or formalin fixed/paraffin embedded (FFPE) tissues. Sequencing was performed on Illumina HiSeqX or NovaSeqX instruments.

  Dataset EGAD50000000496

• Whole-genome sequencing of primary mediastinal large B-cell lymphoma

  To understand the molecular pathogenesis of Primary mediastinal large B-cell lymphoma (PMBCL), we performed whole-genome sequencing of 10 PMBCLs from 8 patients including 2 relapsed tumors.

  Study EGAS50000000340

• WGS of primary mediastinal large B-cell lymphoma

  This dataset includes 19 bamfiles of tumor, relapsed tumor and normal samples derived from 7 patients.

  Dataset EGAD50000000494

• Profiling of Peritoneal Metastases from Gastric Adenocarcinoma Identified Molecular Subtypes

  Peritoneal carcinomatosis (PC) occurs frequently in gastric adenocarcinoma (GAC) patients and confers poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. Here we characterized exome/transcriptome/immune landscapes of PC cells from 43 patients.

  Study EGAS00001003180

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC -- CA209-010

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Study EGAS00001004291

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC -- CA209-009

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Study EGAS00001004290

• Single-Cell RNA-seq of Primary High Grade Serous Carcinoma

  Single-cell RNA Sequencing of CD45- cancer cells.

  Study EGAS50000000068

• A mechanistic classification of clinical phenotypes in neuroblastoma

  Clinical courses of the pediatric tumor neuroblastoma range from fatal progression to spontaneous regression. To gain insights into the pathogenesis of these divergent subtypes, we performed massively parallel sequencing of 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208/416 cases. We observed that telomere maintenance and mutations in RAS or p53 pathway genes strongly affected disease courses. Fatal outcome occurred only in the presence of telomere maintenance, whereas patients whose tumors lacked such mechanisms had excellent outcome. In patients with telomere maintenance-positive tumors, survival was dramatically inferior when additional RAS/p53 pathway mutations were present. By contrast, spontaneous regression occurred both in the presence and absence of RAS/p53 pathway mutations in patients with telomere maintenance-negative tumors. Together, our data provide a precise mechanistic classification of clinical neuroblastoma phenotypes based on telomere maintenance mechanisms and genetic alterations of the tumor.

  Study EGAS00001003244

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Oesophageal_adenocarcinoma

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute (40X and 20X depth respectively). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003702

• Follicular Lymphoma Whole Genome and Transcriptome Sequencing

  Study EGAS00001006646

• Whole transcriptome sequencing of 78 follicular lyphoma tumours

  This data set includes RNAseq from 77 follicular lymphoma tumours. All tumours were fresh frozen. Libraries were constructed by enriching for poly-A transcripts and sequenced as 75bp paired end reads on an Illumina HiSeq 2500 instrument.

  Dataset EGAD00001010894

• Genomic landscape and molecularly-informed therapy in thymic carcinoma and other advanced thymic epithelial tumors (H021, HIPO)

  The molecular landscape of malignant thymic epithelial tumors (TET) is largely unknown. To better understand and target these clinically challenging entities, we characterize 81 patients harboring 46 thymus carcinomas (TC), 8 neuroendocrine tumors of the thymus (NET) and 27 thymomas using WGS/WES, transcriptome and methylome analysis. TC harbor different molecular alterations compared to thymoma and NET and have higher tumor mutational burden than thymomas. 14/76 TET patients show (likely) pathogenic germline alterations. Composite biomarker analysis indicates homologous repair deficiency in a subset of patients. We identify immunologically hot and cold TC. Cold TC show significantly shorter overall survival. 71/81 patients receive molecularly-informed therapy recommendations, which are applied in 28/71 cases leading to a DCR of 60% and an ORR of 24% (both n=25). 8/23 patients reach PFS ratios > 1.3, seven of them having TC.

  Study EGAS00001006408

• Comprehensive Characterization of Early Relapse and End-Stage Relapsed Refractory Multiple Myeloma (HIPO K08K/H067/H021+nonHIPO)

  Study EGAS00001007469

• Gut microbiome sequencing in patients receiving combination immune checkpoint blockade

  This dataset contains 16S and WMS data for gut (fecal) microbiome samples taken from patients treated with combined anti-CTLA-4 and anti-PD-1 checkpoint blockade for advanced melanoma.

  Study EGAS00001004885

• Integrative_Oncogenomics_of_Multiple_Myeloma

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from Multiple Myeloma patient DNA and matched normal DNA from the same patients. Two lanes of Illumina GA sequencing will be performed on the resulting exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes.

  Study EGAS00001000036

• 463 newly diagnosed patients with Multiple Myeloma underwent whole exome sequencing of tumour and peripheral blood DNA.

  463 newly diagnosed patients from the UK Myeloma XI clinical trial (NCT01554852) underwent whole exome sequencing plus targeted capture of the IGH/K/L and MYC loci. 200 ng of DNA were processed using NEBNext DNA library prepartion kit and hybridised to the SureSelect Human All Exon V5 Plus. Four samples were pooled and run on one lane of a HiSeq 2000 using 76-bp paired end reads. DNA from CD138+ selected bone marrow cells (myeloma tumour) as well as peripheral white blood cells were analysed and somatic mutations detected.

  Study EGAS00001001147

• Targeted panel data for newly diagnosed myeloma patients.

  Genomic abnormalities in MM are common and can affect a patients outcome. Here we have performed targeted sequencing on xx patient tumor samples and matched control DNA. The targeted panel consists of ~160 genes and copy number regions, as well as key regions of chromosomal translocation including IGH, IGK, IGL and MYC. Using mutation, copy number, and translocation information we have been able to identify abnormalities that affect prognosis including bi-allelic inactivation of TP53 and rearrangements involving MYC.

  Study EGAS00001002859

• 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

• WES of melanoma tumors treated with combined immune checkpoint blockade

  This study of pre-treatment melanoma tumor samples from patients subsequently treated with combined anti-CTLA-4 and anti-PD-1 checkpoint blockade sought to identify genomic biomarkers of response to therapy. A total of 26 tumor and matched normal samples underwent whole exome sequencing.

  Study EGAS00001003857

• 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

• Primary central nervous system lymphoma (PCNSL) biopsies show heterogeneity in gene expression profiles, genetic subtypes, and in vitro drug sensitivity to kinase inhibitors

  Primary central nervous system lymphoma (PCNSL) is an aggressive large B-cell lymphoma, most often of the activated B cell (ABC) subtype, but with limited tumor biology studies due to small biopsy size and lack of strict cohort definition. Here we examined the genetic heterogeneity of 29 HIV- EBV- PCNSL tumors using whole exome sequencing (WES). We compared these tumors to 5 cell lines comprised of two human PCNSL cell lines (TK and HKBML) and three systemic activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) (OCI-Ly3, TMD-8, HBL-1).

  Study EGAS50000000312

• Whole exome sequencing (WES) of EBV- primary central nervous system lymphoma (PCNSL)

  This dataset contains whole exome sequencing (WES) of 29 HIV- EBV- primary central nervous system lymphoma (PCNSL) tumors and 5 activated B-cell-like PCNSL (ABC-PCNSL) and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cell lines (TK, HKBML, OCI-Ly3, HBL-1, TMD-8). Cases with secondary involvement of the CNS were excluded. DNA was extracted with AllPrep DNA/RNA FFPE kit and libraries were prepared using the Agilent SureSelect Human All Exon v6 + UTR kit. Paired end reads were aligned to GRCh37 using bwa mem v.0.7.17, and reads were sorted and duplicated were marked in the final BAM files. Access to this data is controlled. There are a number of steps that a researcher must take to obtain access to this data, including execution of a Data Access Agreement between the institutions. The process is overseen by the Technology Development Office; please contact our general email address TDOadmin@phsa.ca. Please only click the "request data" button on the EGA website after a Data Access Agreement is fully executed.

  Dataset EGAD50000000451

• G-SAM: Transcriptional Evolution of Glioblastomas Treated With Standard of Care

  Collection of mostly matching primary and recurrent glioblastoma RNA-seq sample pairs, also matching with an earlier DNA sequencing study

  Study EGAS00001005436

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma___2

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003542

• Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

  Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements most patients die of their disease. While immune checkpoint blockade has become part of the standard of care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment in the early disease setting remain largely unknown. We hypothesized a higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with non-metastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n=21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by 4 cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well-tolerated, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent PD-L1 blockade and the subsequent combination with chemotherapy on the tumor microenvironment. A total of 21 patients were included, of whom 20 patients underwent surgery and were evaluable for the secondary pathologic response and survival endpoints, while 19 were evaluable for exploratory translational analyses. A major pathologic response (MPR, ≤10% residual viable tumor) was observed in 14/20 (70%; 95% CI 46-88%) patients, including 9 (45%; 95% CI 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13/14 responders were alive and disease-free, while 5/6 nonresponders had died due to disease recurrence. Notably, baseline PD-1+CD8+ T cell infiltration was significantly higher in responders than in nonresponders, and comparison of the tumor microenvironment alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy revealed that increased immune activity was achieved upon single-agent PD-1/L1 axis blockade. Based on these data, anti-PD-L1 plus chemotherapy warrants further exploration in patients with non-metastatic G/GEJ cancer, and these results call for validation in a larger cohort.

  Study EGAS50000000168

• Single-nuclei gene-expression analysis of pheochromocytoma and paraganglioma links tumor subtypes with tumor microenvironment

  Pheochromocytomas and paragangliomas (PCPG) are rare neuroendocrine tumors associated with autonomic nerves. We used single nuclei-RNA-seq (snRNA-seq) for analysis of 30 PCPG representing 13 known driver genes, plus two normal adrenal medullas to dissect cell composition, refine PCPG subtypes and compare PCPG and normal tissue expression. Incorporating bulk-tissue and snRNA-seq data we identified seven PCPG gene-expression subtypes with genotype and cell type associations. The tumor microenvironment reflected HIF pathway activation and neovascularization by detection of abundant tip-like endothelial cells and pericytes concordant with VEGFA expression in neoplastic cells with mutations in VHL, genes encoding SDH subunits and MAML3-fusions. Macrophages were abundant in PCPG with distinct tumor-associated features. Schwann-cell-like cells were also enriched in some subtypes. The transcriptional profile of neoplastic PCPG cells resembled normal chromaffin cells but early chromaffin and neuroblast cell markers were expressed in some subtypes including GPR139, a putative therapeutic target for a subset of pseudohypoxic PCPG.

  Study EGAS00001005861

• Genomic and epigenomic study of Japanese renal cell carcinoma including WGS, RNA-seq, ATAC-seq, and methyl-seq

  We performed whole-genomic and transcriptomic sequencing of more than 100 Japanese renal cell carcinoma (RCC) cases, including clear cell RCC, papillary RCC, chromophobe RCC, and TFE3-translocated RCC. In addition, we conducted epigenome sequencing analyses: the assay for transposase-accessible chromatin sequencing (ATAC-seq) and enzymatic methyl sequencing.

  Study EGAS00001006919

• Single-cell and bulk RNA-sequencing of nivolumab-treated glioblastoma

  Glioblastoma is a highly aggressive type of brain tumour for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected glioblastoma patients, and it is currently not well understood what separates the few responders from the non-responders at the cellular and molecular level. Here we investigate the phenotypic and transcriptional evolutionary dynamics at single-cell resolution during nivolumab immune checkpoint treatment of eight glioblastoma patients enrolled in a translational phase I/II clinical trial.

  Study EGAS00001007110

• Single-cell RNA-sequencing of nivolumab-treated glioblastoma

  Single-cell RNA-sequencing of 8 patients, from primary and relapse tumour (total of 16 samples). Patients were treated with nivolumab prior to relapse surgery.

  Dataset EGAD00001010843

• Bulk RNA-sequencing of nivolumab-treated glioblastoma

  Bulk RNA-sequencing of 30 relapse tumour samples. 20 patients were treated with nivolumab prior to relapse surgery, while 10 patients are control patients.

  Dataset EGAD00001010844

• DCLRE1B/Apollo germline mutations associated with renal cell carcinoma

  Highlights of Bories et al. article submitted to BBA - Molecular Basis of Disease: We identified 2 germline mutations in the DCLRE1B gene encoding the Apollo protein by Whole Exome Sequencing (WES) in two families with inherited clear-cell Renal Cell Carcinoma. Our study suggests a putative link between DNA repair, telomere protection and renal oncogenesis.

  Study EGAS50000000216

• DCLRE1B/Apollo germline mutations associated with renal cell carcinoma impair telomere protection.

  We identified 2 germline mutations in the DCLRE1B gene encoding the Apollo protein by Whole Exome Sequencing (WES) in two families with inherited clear-cell Renal Cell Carcinoma. The raw data submitted here corresponds to WES performed on Genomic Platform at Gustave Roussy Institute.

  Dataset EGAD50000000311

• Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

  ABACUS is a single arm phase 2 study that investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in 95 patients with muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint.

  Study EGAS00001004445

• Characterisation of the genetic landscape of cutaneous leiomyoma and leiomyosarcoma - Leiomyosarcoma RNA

  Cutaneous leiomyoma (cLM) and leiomyosarcoma (cLMS) are rare benign and malignant soft tissue neoplasms showing smooth muscle differentiation, respectively, that arise from mesenchymal cells in the dermis and subcutis. Through whole exome sequencing of cLM and cLMS cases, we observed distinct differences between the somatic mutational profile of these tumour types. FH was identified as a driver gene in cLM with genetic alterations of FH occurring via somatic point mutation, somatic copy number loss, biallelic inactivation and germline point mutations. TP53 and RB1 were identified as driver genes in the cLMS cohort, with genetic alterations of TP53 occurring via somatic and germline point mutations, copy number loss and biallelic inactivation. Using RNA-sequencing, we identified recurrent gene fusions, including CRTC1/3-MAML2 in cLMS and a novel MYLK-MAP3K2 fusion. Analysis of the cell types present in the tumour microenvironment revealed a significantly increased presence of macrophages and decreased presence of myeloid dendritic cells in the cLMS cohort relative to the cLM cohort. Additionally, we identified common driver genes between cLMS and LMS from other sites. Thus, we provide the first in-depth profile of the genetic landscape of cLM and cLMS.

  Dataset EGAD00001014790

• Targeted capture sequencing to identify MYC, BCL2, and BCL6 rearrangements in non-Hodgkin lymphoma

  Targeted capture sequencing of 364 samples representing a mix of Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and high-grade B-cell lymphomas with MYC and BCL2 or BCL6 rearrangements. Capture space covers 3.5 Mb of the human genome including regions around MYC, BCL2, BCL6, PAX5, and IGH/K/L.

  Dataset EGAD50000000489

• Clinical outcomes in ctDNA-positive urothelial carcinoma patients treated with adjuvant immunotherapy

  Minimally invasive approaches to detect residual disease after surgery are urgently needed to select patients at highest risk for metastatic relapse for additional therapies. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease (MRD) and relapse,1-3 but its clinical value has yet to be demonstrated in a randomised clinical trial. We evaluated outcomes in post-surgical ctDNA-positive (+) patients in a randomised phase III trial of adjuvant atezolizumab versus observation. IMvigor010 enrolled 809 patients with muscle-invasive urothelial carcinoma and did not meet its primary endpoint of disease-free survival (DFS) in the intent-to-treat population. Within the study, an exploratory planned analysis of prospectively collected plasma was performed, which tested the utility of ctDNA to identify patients who may benefit from adjuvant atezolizumab treatment. ctDNA was measured at the start of therapy (cycle 1 day 1; C1D1) and at week 6 (cycle 3 day 1; C3D1), and 581 patients were evaluable for ctDNA. The prevalence of ctDNA positivity at C1D1 was 37% (n=214), and ctDNA positivity identified patients with poor prognosis (observation arm DFS HR= 6.19 (4.29, 8.91), p<0.0001). Here we show that ctDNA(+) patients had improved DFS and overall survival (OS) with atezolizumab versus observation (DFS HR= 0.56 (0.41-0.77); p=0.0003 and OS HR= 0.58 (0.4-0.86); p=0.0063). No difference in DFS or OS between arms was noted for ctDNA-negative patients. The rate of ctDNA clearance was higher with atezolizumab (18%) versus observation (4%) (p=0.0041). Transcriptomic analysis revealed that tumours from ctDNA(+) patients had higher expression of cell cycle and keratin genes. Within the ctDNA(+) patient population in the atezolizumab arm, non-relapsing patients were further enriched in prominent immune response signatures including PD-L1, IFNG, CXCL9, and high tumour mutational burden, whereas relapse was associated with angiogenesis and fibroblast-transforming growth factor-beta signatures (F-TBRS). TCGA molecular subset analysis revealed increased efficacy of atezolizumab in patients with basal-squamous tumours, consistent with underlying tumour-immune contexture. Together these findings suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in this high-risk ctDNA(+) population. These findings, if validated in other settings, would shift approaches to post-operative cancer care.

  Study EGAS00001004997