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• Exploration of CNV’s and SNV’s in cancers with well-known genetic rearrangements: Identification of additional genetic changes in rearrangements-driven cancer

  Specific cancers are well known to have specific gene rearrangements. Representative cancer is chronic myeloid leukemia (CML) which is famous for BCR/ABL gene rearrangements. By the way, also genetic rearrangements are not infrequently found in acute leukemia, and those include CBFB/MYH11 rearrangements, PML/RARA rearrangements, AML/ETO rearrangements, and BCR/ABL rearrangements. The situation is same is for lung adenocarcinoma of non-smokers and prostate cancers, and ALK and RET gene rearrangements are recently found. However, not all these rearrangements are sufficient to develop cancer, and it is suggested that some genetic aberrations are required for the development and progression of cancer in addition to these genetic rearrangements. In this study, we have a plan to explore the existence of additional genetic changes including single nucleotide variants (SNV’s) and copy number variations (CNV’s) in cancers with specific genetic rearrangements so as to define additional genetic changes that confer full oncogenic potential to cancer cells. So as to look at SNV’s and small indels, we are going to use whole exome sequencing (WES) data. And as for CNV’s, we are going to use array-CGH data. Also, to check the functionality of these genetic changes, we are going to use whole transcriptome data (WTS). In addition, in samples with whole genome sequencing (WGS ) data, we are going to explore genetic changes in intronic regions also. In fact, we sequenced 10 AML samples which are known to have specific genetic rearrangements. Analysis of these WGS, WES and WTS data are under the way. If we have a chance to access WES, array-CGH and WTS data of other cancer samples with specific genetic rearrangements, we would be able to compare additional genetic changes required for oncogenesis in cancer cells with various genetic rearrangements. We hope this result will enlighten our understanding of cancer genetics further.

  Study EGAS00001000673

• ctDNA quantification in Ewing sarcoma patients

  Background. Treatment stratification and response assessment in pediatric sarcomas has relied on imaging studies and surgical/histopathological evidence of vital tumor cells. Such studies and evidence collection processes often involve radiation and/or general anesthesia in children. Cell-free circulating tumor DNA (ctDNA) detection in blood plasma is one available method of so-called liquid biopsies that has been shown to correlate qualitatively and quantitatively to some extent with the existence of vital tumor cells in the body. Our clinical observational study focused on the utility and feasibility of ctDNA detection in pediatric Ewing sarcoma (EWS) as a marker of minimal residual disease (MRD). Patients and Methods. We performed whole genome sequencing to identify the exact breakpoints in tumors known to carry the EWS-FLI1 fusion gene. Patient-specific fusion breakpoints were tracked in peripheral blood plasma using digital droplet PCR (ddPCR) before, during, and after therapy in six consecutive children and young adults with EWS. Presence and levels of fusion breakpoints were correlated with clinical disease courses. The genetic changes in the tumors were defined, and inter- and intra-individual changes in the tumor DNA copy loads were observed over time. Results. We show that the detection of ctDNA in the peripheral blood of EWS patients i) is feasible in the clinical routine and ii) allows for the longitudinal real-time monitoring of MRD activity in children and young adults. Although changing ctDNA levels correlated well with clinical outcome within patients, between patients, a high variability was observed (inter-individually) for the six patients described here. Conclusions. ctDNA detection by ddPCR is a highly sensitive, specific, feasible, and highly accurate method that can be applied in EWS for follow-up assessments as an additional surrogate parameter for clinical MRD monitoring and, potentially, also for treatment stratification in the near future.

  Study EGAS00001006433

• One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids

  Recent optimization of CRISPR/Cas9-mediated genome engineering has resulted in the development of base editors that can efficiently mediate C>T and A>G transitions. Combining these genome engineering tools with human adult stem cell (ASC)-derived organoid technology holds promise for disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived hepatocyte, endometrial and intestinal organoids. First, using conventional and evolved Cas9-variants, we show efficacy of both cytosine and adenine base editors and use them to model four hot-spot point mutations in CTNNB1 in hepatocyte organoids. Next, we apply C>T base editors in endometrial organoids to insert nonsense mutations in PTEN and demonstrate tumorigenicity even in the heterozygous state. Furthermore, we use cytosine base editors for simultaneous oncogene activation (PIK3CA) and tumor-suppressor inactivation (APC and TP53). To increase the flexibility of base editor multiplexing, we then combine SpCas9 and SaCas9 base editors for simultaneous C>T and A>G editing at individual target sites. Finally, we show the power of base editor multiplexing by modeling colorectal tumorigenesis in a single step by simultaneously transfecting sgRNA’s targeting four cancer genes. Seven clonal organoid lines and one bulk wild-type control sample were paired-end whole-genome sequenced using the Illumina Novaseq 6000 system. We sequenced four clonal intestinal organoid lines harbouring engineered TP53 and FBXW7 mutations as well as three lines targeted for oncogenic APC/TP53/PIK3CA/SMAD4 mutations. This WGS showed, as previously reported, a genome-wide increase in C>T mutations due to C>T base editor off-target activity, which is not enriched in predicted off-target regions based on the sgRNA sequences. Furthermore, we confirmed the absence of editing-induced driver mutations and lack of off-target mutational hotspots created by the genomic engineering.

  Study EGAS00001006886

• Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

  Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

  Study EGAS00001006904

• A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease

  Recurrent acute pain, or vaso-occlusive pain crisis (VOP), is the most common complication of sickle cell disease and correlates strongly with increased hospital visits and early mortality (PMID: 1710777). While the genetics of VOP in sickle cell patients has been studied (PMID: 29205277, 27883292, 25102390, 30079801, 22925497, 29531649, 29620434, 19468207, 20172753, 22576309, 30031848, 24136375, 27603703, 29559808), it is not fully understood.Using whole genome sequencing, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10−14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10−13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.For publications, written, and/or oral presentations resulting from use of this data, please cite the following information: "The original data description for A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease can be found here: (Journal Citation Blood Adv. 2021 Jul 27;5(14):2839-2851) (PMID: 34283174)."

  Study phs002470

• DAC for Central African ancient demography processes NGS dataset

  Title DAC Ancient tree-topologies and gene-flow processes among human lineages in Africa Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Short description The Data Access Committee for acess to genotype and sample information used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa" by Gwenna Breton et al. 2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. DNA samples from individuals were collected with the subjects’ informed consent following the Declaration of Helsinki guidelines and approved by the following Ethics committees: Institut de Recherche pour le Développement (IRD, France); Cameroon Ministry of Scientific Research and Technology; Central African Republic Ministère de l’Enseignement Supérieur et de la Recherche Scientifique; France Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation (Comité de Protection des Personnes DC-2016-2740); French Commission Nationale Informatique et Liberté CNIL (declaration n°1972648); Uganda National Council for Science and Technology; Institutional Review Board of the University of Chicago Biological Sciences Division and the Pritzker School of Medicine University of Chicago Hospitals (protocol number 16986A); Committee for the Protection of Human Subjects of the Trustees of Dartmouth College and the Dartmouth-Hitchcock Medical Center (protocol number 22410); Human Research Ethics Committee (Medical) at the University of the Witwatersrand, Johannesburg (Protocol Numbers: M980553, M050902, M090576, M10270, M180654); Working Group of Indigenous Minorities in Southern Africa (WIMSA); South African San Council (SASC); and the Swedish Ethical Review Authority (Dnr 2019-05174). Requests for accessing all or part of the Central African data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), should be addressed to the DAC providing: 1) Data can only be used to explore human genetic evolution, evolutionary ecology and population history 2) The research institution where data will be stored and were analyses will be conducted. 3) The detailed coordinates of the researcher responsible for data storage and analyses. 4) A description (max 20 sentences) of the scientific finality and context of the project and classes of methodological analyses that will be performed to achieve it using the requested data. 5) When applicable, mention also other previously published data sets that will be used jointly with the requested datas et For accessing any or all the Central African genetic data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), the requester hereby ensures that: 1) Individual donor privacy should be respected at all times. Data cannot be made publicly available under any circumstances. 2) Data cannot be shared nor transferred to a third party without re-applying for eGA access to the DAC. 3) No direct or indirect commercial use of the data can be made 4) No individual medical genetics or disease diagnostics can be performed with the data 5) No medical or legal forensic investigations can be conducted with the data 6) No genealogical research can be conducted with the data (e.g. no paternity nor maternity testing, no genetic identification, no search of relatives using other datasets) 7) Appropriate citation of the article and data set used for any scientific communication using the data 8) Data is destroyed after the completion of the project. Any further re-use of the data is subject to a novel application to the DAC.

  Dac EGAC50000000447

• Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients (LuCaP cell line data)

  Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX). In silico analyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validated in vitro. Critically, we identified the pan-HDAC inhibitor, vorinostat to be effective in decreasing tumor cell proliferation both in vitro and in vivo. Moreover, we uncovered evidence for HDAC3 working together with Glucocorticoid Receptor (GR) as a potential mechanism for this therapeutic effect. These findings demonstrate rationale for new therapeutic strategies including HDAC inhibitors to improve patient outcome in advanced stages of mCRPC. Project Goal: We identified H3K27ac regions associated with resistance in patient samples. Extensive analysis of these regions suggested that HDAC3 may play a role in resistance. To test this, we analyzed ChIP-seq and RNA-seq from cell lines generated from PDX LuCaP samples (recapitulating resistant and non-resistant) to validate findings in patient samples. ChIP-seq samples were used to verify the signals identified from specific factors, such as H3K27ac, AR, FOXA1, GR and HDAC3, their association with resistance and possible mechanisms of action. RNA-seq samples were analyzed to determine the effect of AR signaling in these samples in specific genes in the H3K27ac resistance-associated regions.

  Study EGAS50000000917

• Limited Association between HRR Gene Alterations and HRD in Molecular Tumor Board Cancer Samples: Who should be tested for HRD?

  Alterations in Homologous Recombination Repair (HRR) Pathway genes have been found to be associated with HR-Deficiency (HRD), which is an approved biomarker for PARP Inhibitor (PARPi) treatment. The aim of a Molecular Tumor Board (MTB) is to identify molecular alterations in cancer patients with advanced tumors that may suggest off-label treatment options. So far, few studies have analyzed the presence of HRR gene mutations and their association with HRD outside of clinical studies. Currently, no data on HRD testing in the setting of a MTB have been published. For the present study, a cohort of 237 patients encompassing 24 different tumor entities was collected from the MTB of the Comprehensive Cancer Center Erlangen-EMN. We show that an elevated Genomic Instability Score (GIS ≥ 42) can occur in samples with and without mutations in HRR-related genes. Overall, 38.1% of cancer samples with BRCA1/2 mutations, 10.9% of tumors with alterations in HRR genes other than BRCA1/2, and 4.3% of cancer samples without HRR gene mutations harbored an elevated GIS. Notably, our data show that various inactivating BRCA1/2 mutations are not associated with an elevated GIS. Taken together, panCancer assessment of HRD in addition to BRCA1/2 and other HRR gene mutational analysis is recommended to guide decisions regarding PARPi treatment. Further studies are needed to establish thresholds for GIS in non-ovarian cancer entities. Finally, HRD can be observed in 4.3% of BRCA1/2 and other HRR gene wildtype cancer samples, and may emerge as an independent biomarker for PARPi in the future.

  Study EGAS00001008063

• Pharmacological and genomic profiling identifies NFκB-targeted treatment strategies for mantle cell lymphoma

  Mantle cell lymphoma (MCL) is an aggressive malignancy characterized by poor prognosis, underscoring the need for novel therapeutic strategies1. In this study, we employed large-scale pharmacological profiling of 16 pathway inhibitors across more than 100 hematological cell line models to identify novel therapeutic approaches. This screen identified a subset of MCL cell lines that were highly sensitive to the B-cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin (STN), which are currently in clinical trials2, 3. Sensitive MCL models exhibited chronic activation of the CARD11-BCL10-MALT1 (CBM) complex and dependency on downstream classical NFκB signaling. In contrast, insensitive cell lines displayed activation of the alternative NFκB pathway. Massively parallel transcriptome sequencing identified mutations in negative regulators of the alternative NFκB pathway in ibrutinib-insensitive cell lines. Notably, sequencing of 165 MCL patient samples revealed that components of the alternative NFκB pathway, particularly TRAF2 and BIRC3, are mutated in roughly 15% of MCL patients. Functional analyses of patient-derived BIRC3 mutant alleles indicated that these are loss-of-function mutants that constitutively activate alternative NFκB signaling. While being associated with insensitivity to ibrutinib, genetic lesions in the alternative pathway conferred dependence on NIK, a kinase that mediates signaling downstream of the TRAF2/3-BIRC2/3 complex. Thus, NIK represents a novel therapeutic target for MCL treatment, particularly for tumors refractory to BCR pathway inhibitors. Collectively, these findings reveal a pattern of mutually exclusive activation of the CBM-NFκB or alternative NIK-NFκB pathways in MCL and provide critical insights into patient stratification strategies for NFκB-pathway targeted agents.

  Study EGAS00001000622

• Biomarker Screen for Efficacy of Oncolytic Virotherapy in Patient-derived Pancreatic Cancer Cultures

  Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking. We screened fourteen patient-derived PDAC cultures for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H 1PV using live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays. Sensitivity was correlated with transcriptome profiles to identify potential predictive biomarkers for response to OVT. Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the basal-like molecular subtype, the quasi-mesenchymal subtype of PDAC was more sensitive to H-1PV, jin-3, and T-VEC. Expression of viral entry receptors did not correlate with sensitivity to OV treatment. Rather, cellular pathways controlling immunological, metabolic, and proliferative signalling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas cGAS expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures.

  Study EGAS00001007001