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• PSCP_bisulphite analysis in hESCs (2018-08-13)

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-08-13.

  Dataset EGAD00001004295

• Genomic evolution and transcriptional changes in the evolution of prostate cancer into neuroendocrine and ductal carcinoma types (RNAseq)

  Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuro-endocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease and the former often arises on a background of androgen deprivation therapy, although it can al-so arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tis-sue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with 3 longitudinal samples over 5 years. Case 2 was a single time point after development of treatment related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all sam-ples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for the ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small cell neuroendocrine and ductal prostatic carcinoma can have a common an-cestry and the process of evolution over time. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

  Study EGAS00001007428

• Patient-derived pediatric brain tumor organoids faithfully recapitulate primary tumors

  Extensive molecular analysis by many groups has revealed a heterogeneous landscape of embryonal brain tumors, including medulloblastoma (MB) and atypical teratoid/rhabdoid tumor (ATRT). MB, the most common malignant pediatric brain tumor, is comprised of four molecularly distinct subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3), and Group 4 (G4). Among these, MB-SHH harboring MYCN amplification and TP53 mutation and MB-G3 with MYC overexpression or amplification constitute the most aggressive tumors, have the poorest clinical outcomes, and lack effective therapeutic options for recurrent disease. Here we describe the establishment of tumor organoid (TO) models from patient-derived orthotopic xenografts (PDOX) of MYCN-amplified and TP53-mutant MB-SHH, MYC-amplified MB-G3 and two ATRT which all grew in mice when reimplanted into the cortices of naïve recipient animals (TOX). Methylation, bulk and single-cell RNA sequencing, and whole genome sequencing demonstrated that TOs and TOXs faithfully recapitulated the molecular landscape and heterogeneity of PDOXs and primary patient tumors compared to established cell lines. The development of TOs will facilitate in vitro high-throughput drug or CRISPR screens without the need for use tumor-bearing mice. This will also accelerate the identification and validation of new vulnerabilities and in vivo preclinical testing toward clinical trials.

  Study EGAS00001008305

• The Spatial Heterogeneity in Multiple Myeloma - from the Subclonal Architecture to the Immune Microenvironment (partly hipo_K08K)

  Multiple myeloma (MM) cells show pronounced heterogeneity not only within a given patient but also between spatially separated tumor loci in the bone marrow. Understanding this spatial heterogeneity is emerging as a critical challenge for the successful treatment of the disease. Yet, our understanding of spatial differences in the subclonal architecture, molecular signatures and interactions with the tumor microenvironment remains very limited. To address this shortcoming, we performed bulk and single-cell multi-region sequencing, including random bone marrow samples from the iliac crest and paired imaging-guided focal lesion specimens from 15 newly diagnosed MM patients. We found a median of 5 subclones per patient and unique subclones in focal lesions. Central features of spatial heterogeneity included a consistent down-regulation of the chemoattractant cytokines CXCL7 and CXCL12 in focal lesion tumor cells as well as a significant depletion of macrophages in the focal lesion microenvironment. In contrast, a site-specific expansion of T-cell clones was not detected in focal lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity with potential implications for immunotherapies and molecular studies analyzing the role of gene signatures and MM-microenvironment interactions in disease progression.

  Study EGAS00001006090

• Long-term organoid culture of a small intestinal neuroendocrine tumor rna-seq

  Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.

  Study EGAS00001007108

• Ewing and Ewing-like-sarcoma tumoroid biobank reveals distinct drug sensitivities: translocation makes the difference

  Ewing sarcoma (ES) and Ewing-like sarcomas (ELS) are highly aggressive tumors found in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeutic regimen. Currently, there is a lack of preclinical cell models that can predict drug response of these entities in vitro. Here, we describe a pediatric ES and ELS tumor organoid (tumoroid) biobank containing tumoroids with different translocations, including EWSR1::FLI1, EWSR1::ERG, CIC::DUX4, and BCOR-rearrangements. Using histology, whole genome sequencing and RNA sequencing, we demonstrate that these tumoroids retain key properties of their matching patient tumors. In addition, we traced tumor subclones in the tumoroids across patient-matched longitudinal samples, which showed that cellular heterogeneity was maintained. We subsequently performed drug screening on the tumoroid models, which unveiled entity-specific drug sensitivity to various cytotoxic compounds and targeted compounds, including MCL-1 inhibitors for CIC::DUX4 sarcomas. Taken together, this newly established ES and ELS patient-derived tumoroid biobank generates a unique source of material for future basic cancer research and drug-screening.

  Study EGAS00001007941

• Adult-type Granulosa Cell Tumour of the Ovary

  A recurrent mutation in FOXL2 (c.402C>G; p.C134W) is present in over 95% of adult-type granulosa cell tumours (AGCTs). In contrast, various loss-of-function mutations in FOXL2 lead to the development of blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). BPES is characterized by an eyelid malformation often accompanied with primary ovarian insufficiency but not granulosa cell tumours. Two recent studies suggest that FOXL2 C402G is a gain or change-of-function mutation with altered DNA-binding specificity. Another study proposes that FOXL2 C402G is selectively targeted for degradation inducing somatic haploinsufficiency suggesting its role as a tumour suppressor. The latter study relies on data indicative of an FOXL2 allelic imbalance in AGCTs. Here we present RNA-seq data as genetic evidence that no real allelic imbalance is observed at the transcriptomic level in AGCTs. Additionally, there is no loss of protein expression in tumours harboring the mutated allele. These data and other features of this mutation as compared to other oncogenes and tumour suppressor genes argue strongly against FOXL2 being a tumour suppressor in this context. Given the likelihood that FOXL2 C402G is oncogenic, targeting the variant protein or its downstream consequences is the most viable path forward to identifying an effective treatment for this cancer.

  Study EGAS00001005414

• A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

  The PRDM13 (PR Domain containing 13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

  Study EGAS00001005878

• Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALS

  Neuroinflammation is an important hallmark in amyotrophic lateral sclerosis (ALS). Experimental evidence has highlighted a role of microglia in the modulation of motor neuron degeneration. However, the exact contribution of microglia to both sporadic and genetic forms of ALS is still unclear. We generated single nuclei profiles of spinal cord and motor cortex from sporadic and C9orf72 ALS patients, as well as controls. We particularly focused on the transcriptomic responses of both microglia and astrocytes. We confirmed that C9orf72 is highly expressed in microglia and shows a diminished expression in carriers of the hexanucleotide repeat expansion (HRE). This resulted in an impaired response to disease, with specific deficits in phagocytic and lysosomal transcriptional pathways. Astrocytes also displayed a dysregulated response in C9orf72 ALS patients, remaining in a homeostatic state. This suggests that C9orf72 HRE alters a coordinated glial response, which ultimately would increase the risk for developing ALS. Our results indicate that C9orf72 HRE results in a selective microglial loss-of-function, likely impairing microglial-astrocyte communication and preventing a global glial response. This is relevant as it indicates that sporadic and familial forms of ALS may present a different cellular substrate, which is of great importance for patient stratification and treatment.

  Study EGAS00001006711

• T cell landscape definition by multi-omics identifies galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia (CLL)

  Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA- sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.

  Study EGAS00001006864