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• Oral mucosa organoids as a potential model for personalized therapies

  Organoids were established from both tumor and matched wildtype tissue from patients diagnosed with head and neck squamous cell carcinoma (HNSCC). In order to confirm tumor status and identify oncogenic driver mutations, DNA derived of these organoids was sequenced. After validation of tumor identity, organoids were exposed to a range of (targeted) chemotherapeutics and radiotherapy. Differential responses to therapeutics were subsequently correlated to underlying genetic alterations to see if DNA mutation status could be predictive for responses to therapy.

  Study EGAS00001003628

• A Single Cell Transcriptomic Analysis of Human Neocortical Development

  Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We produced single cell transcriptomic profiles for 40,000 cells at mid-gestation to define deep expression profiles corresponding to all known major cell types at this developmental period and compare this with bulk tissue profiles. We identified multiple transcription factors (TFs) and co-factors expressed in specific cell types, including multiple new cell-type-specific relationships, providing an unprecedented resource for understanding human neocortical development and evolution. This includes the first single-cell characterization of human subplate neurons and subtypes of developing glutamatergic and GABAergic neurons. We also used these data to deconvolute single cell regulatory networks that connect regulatory elements and transcriptional drivers to single cell gene expression programs in the developing CNS. We characterized major developmental trajectories that tie cell cycle progression with early cell fate decisions during early neurogenesis. Remarkably, we found that differentiation occurs on a transcriptomic continuum, so that differentiating cells not only express the few key TFs that drive cell fates, but express broad, mixed cell-type transcriptomes prior to telophase. Finally, we mapped neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types in ASD, ID, and epilepsy, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.

  Study phs001836

• Colorectal cancer organoids expressing BRAF (fusion) genes

  Fusion genes may be oncogenic drivers and potential targets for personalized therapies in a variety of cancer types. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. BRAF can be fused to a wide variety of genes, however, BRAF fusions rarely occur in the exact same gene configuration, making assessment of the fusion relevance and decision for drug treatment challenging. Here, we devised a colorectal cancer organoid-based platform to functionally characterize diverse BRAF fusions, containing various partner genes (AGAP3, DLG1 and TRIM24). We compared these BRAF fusions with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We found that 5’ partner choice of BRAF affects cellular localization and intracellular signaling capacities of the fusion genes. The DLG1-BRAF fusion gene showed distinct localization to the plasma membrane and exhibited increased levels of MAPK pathway activation under unperturbed conditions. Furthermore, the different BRAF fusions showed varying sensitivities to the targeted inhibition of ERK and BRAF, with the DLG1-BRAF fusion being the most sensitive. Additionally, RNA-sequencing identified distinct subsets of genes affected by the DLG1-BRAF fusion gene. Importantly, all fusion genes conveyed resistance to the clinically relevant EGFR/HER2/HER4-inhibitor afatinib, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients amenable to cetuximab treatment. In summary, we developed a platform to efficiently assess molecular and cellular effects of fusion genes, and revealed that differential drug responses and distinct gene expression profiles can be induced by different BRAF fusions .

  Study EGAS00001003558

• Transcriptomic analysis of TFEB knockdown in LT-HSC.

  Long-term hematopoietic stem cells (LT-HSC) were sorted from human cord blood and cultured overnight before transduction with lentiviral vectors overexpressing an shRNA against Renilla (shCTRL) or TFEB (shTFEB). Six days later, mCherry+ transduced cells were sorted for RNA extraction and sequencing.

  Study EGAS00001004967

• Single cell RNA sequencing of colorectal cancer patients (KUL3/KUL5)

  Libraries for scRNA-seq were generated using the Chromium Single Cell 3′ or 5′ library and Gel Bead & Multiplex Kit from 10x Genomics. Aimed to profile 5000 cells per library (if sufficient cells were retained during dissociation).

  Study EGAS00001006049

• Whole_genome_sequencing_in_a_multiplex_Crohn_s_disease_family

  In 2009 we identified a four-generation family with over 700 members and 41 affected with Crohn's disease (CD). At the time we sequenced the exome of 6 affected individuals but did not identify any coding variants which appear to explain the high prevalence of disease. Since then we have collected DNA from a large number of additional family members, genotyped linkage arrays on the entire family to refine genomic regions shared by identity by descent and genotyped affected and unaffected members at known CD risk loci identified by Genome Wide Association Studies (GWAS). These analyses have confirmed that a significant unexplained excess of disease remains after accounting for all known genetic factors, and that several regions of the genome are shared by a large fraction of affected individuals. We therefore perform whole genomes sequencing from 8 individuals which will allow us to impute the complete sequence of nearly all the members of the two largest and most severely affected branches of the family.

  Study EGAS00001000060

• Comprehensive genomic and transcriptomic analysis of three synchronous primary tumours and a recurrence from a head and neck cancer patient

  Synchronous primary malignancies occur in a small proportion of head and neck squamous cell carcinoma patients. Here, we analysed three synchronous primaries and a recurrence from one patient, by comparing the genomic and transcriptomic profiles among the tumour samples and determining the recurrence origin. We found remarkable levels of heterogeneity among the primary tumours, and through the patterns of shared mutations, we traced the origin of the recurrence. Interestingly, the patient carried germline variants which might have predisposed him to carcinogenesis, together with a history of alcohol and tobacco consumption. Mutational signature analysis confirmed the impact of alcohol exposure, with Signature 16 present in all tumour samples. Characterisation of immune cell infiltration highlighted an immunosuppressive environment in all samples, which exceeded the potential activity of T cells. Studies such as the one described here have important clinical value and contribute to personalised treatment decisions for patients with synchronous primaries and matched recurrences.

  Study EGAS00001004857

• Defining the metastasome in colorectal cancer: Implications for hypotheses on metastasis evolution and personalized therapy (HIPO-032)

  Personalized cancer therapy aims at individual genetic changes characterizing primary cancers. Still, however, metastasis is the major clinically unmet problem, also due to an incomplete understanding of its molecular evolution.This study is the first to define the metastasis-specific whole genome landscape of human colorectal primary vs. matched metastatic lesions.Protein coding, ncRNA genes and 3’UTRs harbored about a third each of single nucleotide variations (SNVs)/indels, 19% of them being metastasis-specific. We found novel mutational hills among ncRNAs and 3’UTRs, copy number changes able to explain changes in microRNA expression in metastases, and novel metastasis-specific mutations in the 3’UTRs on important cancer signalling genes. Some metastatic lesions showed targetable mutations not detected in the primaries. Analysis of mutual exclusivity patterns supported a model that has progressive alterations in important colorectal cancer genes and revealed new partners. Metastatic lesions were enriched in SNVs, specific structural variations, and alterations in genes affecting cell adhesion and extracellular matrix interaction.Furthermore, a hepatic stellate activation cascade was enriched in metastases, suggesting genetic programs for site-specific colonization. Allele frequency distribution and mutational signature analysis suggests a common ancestor clone to both the primary tumor and the metastasis, with additional mutagenesis ongoing in both sites independently. Taken together, our results significantly add to hypothesis generation on metastasis evolution, and suggest novel metastasis-specific genomic changes which would be missed by current personalized therapy concepts. (HIPO-032)

  Study EGAS00001002717

• Target sequencing of refractory adult Ph-negative B-ALL 1 patient

  We performed target sequensing of the bone marrow samples to gain a better understanding of refractoriness in a case of adult Ph-negative B-ALL

  Study JGAS000483

• Investigation of Brain Nitrogen Metabolism in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1H MRS, DTI, and fMRI

  This is a case controlled, observational study. This project studies cognitive and motor dysfunction in adult and pediatric patients who are female carriers of ornithine transcarbamylase deficiency (OTCD) or are males with late onset presentation (outside of the newborn period) of OTCD, utilizing state of the art MRI (magnetic resonance imaging), a non-invasive technique. This project seeks to improve our understanding of the underlying neural mechanisms that contribute to metabolic, cognitive, sensory and motor abnormalities in urea cycle disorders, which although individually rare, collectively constitute a major cause of neonatal encephalopathy, leading to significant morbidity and mortality. As a result of this study, a greater understanding of the anatomic, cognitive, motor, and biochemical underpinnings of neurologic damage attributable to this metabolic disorder will be gained. Experimental approaches will combine sensory, cognitive and motor testing with structural, functional and molecular magnetic resonance imaging to study symptomatic and asymptomatic heterozygous female carriers of X-linked ornithine transcarbamylase deficiency (OTCD), and late onset hemizygous males. Participants to be included in the studies ranged from ages 7-60 years and were compared to an age-matched typically developed (TD) comparison group. For our research, we use anatomic MRI, functional Magnetic Resonance Imaging (fMRI), and magnetic resonance spectroscopy (MRS) to monitor brain activity. The technique of fMRI provides detailed maps of the brain areas underlying human mental activities. By using fMRI, we are able to observe how the brain is functioning while a person is performing a specific task, such as reading. We can not only observe differences in the structure of the brain, but can also measure differences in brain function and activity as well. This information will ultimately be used to provide a basis for designing more effective interventions and methods for early identification of learning disabilities in patients with OTCD and related disorders. We will also use MRS to study various brain chemicals such as glutamine using the non-invasive MRI imaging techniques.

  Study phs001296