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• multi-OMICs study of a pair of infant monozygotic twins with concordant B-cell ALL

  B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the genetic and the epigenetic landscape of this particular leukemia subtype, we performed whole genome DNA-, B-cell receptor (BCR)-, and DNA bisulfite-sequencing on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

  Study EGAS00001003651

• 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

• 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

• Genetic makeup of agnospheres

  Agnospheres are cultures of cancer stem cells isolated from tissue biopsies from patients with Cancer of Unknown Primary (CUPs). The latter is a lethal malignancy (median survival <1 year), representing approximately the 3% of all cancers, and characterized by metastatic dissemination in the absence of a primary tumor recognizable by a standardized protocol including thorough body imaging and histopathological analysis. Agnospheres are long-term propagated in culture and, after subcutaneous injection into immunocompromised mice, they display high tumorigenicity and quickly reproduce the clinical presentation of the original tumor, featuring a multi-organ metastatic pattern and poorly differentiated histology. The goal of the project is to analyse the mutational profile of agnospheres in detail, as to verify its correspondance with that of the original tumors. Genetic information will be exploited to investigate the genetic drivers of the CUP phenotype, in particular the hypermetastatic ability and the differentiative block.

  Study EGAS00001004868

• Genetic landscape of inherited retinal dystrophies affected cases in Spain

  Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in a Spanish cohort of patients. A retrospective hospital-based cross-sectional study was carried out on IRD affected individuals, referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to all families with available DNA using different molecular techniques. Our study provides the general landscape for IRD in Spain and our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.

  Study EGAS00001005104

• Transcriptome sequencing of Gingivo-buccal Cancer : ICGC-India Project_Batch05

  Transcriptome Sequencing of Gingivo-buccal Cancer: ICGC-India ProjectAs a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Transcriptome sequencing of paired RNA samples – isolated from the tumor and adjacent normal tissues of 28 patients – have been performed. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from adjacent normal and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani.

  Study EGAS00001003285

• Novel mutations in TOP2A in gliomas

  High grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. To better understand glioma pathobiology and find potential therapeutic susceptibilities, we designed a custom- panel 664 cancer- and epigenetics-related genes and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 glioma samples of different malignancy grades. Besides known alterations in TP53, IDH1, ATRX, EGFR genes, we found several novel variants that can be potential drivers in gliomas. In four patients from the Polish glioma cohort, we identified a novel recurrent mutation in the TOP2A gene coding for Topoisomerase 2A in glioblastomas (GBM, WHO grade IV gliomas). The mutation results in a substitution of glutamic acid (E) 948 to glutamine (Q) of TOP2 A and we predicted this E948Q substitution may affect DNA binding and a TOP2A enzymatic activity.

  Study EGAS00001004556

• Rare coding variants in lupus risk genes

  Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

  Study EGAS00001003548

• Mutational signatures of environmental carcinogens in human tissue organoids

  Whole genome sequencing of human tumours has revealed distinct patterns (signatures) of mutations that provide clues to the causative origins of cancer. Some signatures have been attributed to endogenous processes, some to exogenous agents, while a substantial proportion are of unknown origin. Generation of mutational signatures induced in experimental systems can verify the signature assignments and shed light on their origins and mechanisms. We have investigated mutational signatures of environmental carcinogens in human tissue organoid cultures. These 3-dimensional systems retain some of the architecture and functions of the organs from which they are derived, affording the opportunity to observe the effects of carcinogens in both target and non-target organs. There was a lesser requirement for an exogenous metabolizing system, as the cultures were, in most cases, capable of activating test agents. Duplex sequencing eliminated PCR amplification errors from mutational profiles and removed the need to clone carcinogen-treated cultures. Gastric, colon, liver, pancreas and kidney organoids were exposed to benzo[a]pyrene (BaP), aflatoxin B1 (AFB1), aristolochic acid (AAI) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). All four agents induced single-base substitution (SBS) signatures, BaP and AAI induced double-base substitution (DBS) signatures and indel (ID) signatures, and PhIP also induced an ID signature. These signatures were the same in all five organoid types, although there were quantitative differences. A further 13 environmental carcinogens were investigated in human gastric organoids, and signatures were obtained for seven of them: ethylnitrosourea (ENU), methylazoxymethanol acetate (MAM), N-methyl-N′-nitro-N-nitrosoguanidine (MMNG), potassium bromate, glycidamide, styrene oxide and propylene oxide, providing additional insights into processes underlying the causes of human cancer.

  Dataset EGAD00001015616

• Mutational signatures of environmental carcinogens in human tissue organoids – WGS Bulk Normals

  Whole genome sequencing of human tumours has revealed distinct patterns (signatures) of mutations that provide clues to the causative origins of cancer. Some signatures have been attributed to endogenous processes, some to exogenous agents, while a substantial proportion are of unknown origin. Generation of mutational signatures induced in experimental systems can verify the signature assignments and shed light on their origins and mechanisms. We have investigated mutational signatures of environmental carcinogens in human tissue organoid cultures. These 3-dimensional systems retain some of the architecture and functions of the organs from which they are derived, affording the opportunity to observe the effects of carcinogens in both target and non-target organs. There was a lesser requirement for an exogenous metabolizing system, as the cultures were, in most cases, capable of activating test agents. Duplex sequencing eliminated PCR amplification errors from mutational profiles and removed the need to clone carcinogen-treated cultures. Gastric, colon, liver, pancreas and kidney organoids were exposed to benzo[a]pyrene (BaP), aflatoxin B1 (AFB1), aristolochic acid (AAI) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). All four agents induced single-base substitution (SBS) signatures, BaP and AAI induced double-base substitution (DBS) signatures and indel (ID) signatures, and PhIP also induced an ID signature. These signatures were the same in all five organoid types, although there were quantitative differences. A further 13 environmental carcinogens were investigated in human gastric organoids, and signatures were obtained for seven of them: ethylnitrosourea (ENU), methylazoxymethanol acetate (MAM), N-methyl-N′-nitro-N-nitrosoguanidine (MMNG), potassium bromate, glycidamide, styrene oxide and propylene oxide, providing additional insights into processes underlying the causes of human cancer.

  Dataset EGAD00001015630