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• A higher ctDNA fraction decreases survival in regorafenib-treated metastatic colorectal cancer patients

  The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of this study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 out of 14 KRAS positive tumors, in three patients without KRAS mutation in the respective tumor acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (p=0.022; HHR 3.110 (95%CI: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations (SCNA) in advanced cancer patients.

  Study EGAS00001004491

• Chronic lymphocytic leukemia IGHV somatic hypermutation detection by targeted capture next-generation sequencing

  Somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene locus plays a crucial role in determining the prognosis and treatment of patients with chronic lymphocytic leukemia (CLL). A common approach for determining SHM status is multiplex PCR of the IGH gene followed by Sanger sequencing; however, this technique is low throughput, vulnerable to failure, and does not allow multiplexing with other molecular diagnostic assays. Here we designed and validated a DNA targeted capture approach that allows the assessment of IGHV SHM status as a sub-module of a larger next-generation sequencing (NGS) assay. We developed an end-to-end assay that takes as input raw FASTQ files and outputs a report containing IGHV SHM status and V-allele usage following the guidelines of the European Research Initiative on CLL (ERIC). We validated the approach on 35 CLL patient samples, 34 of which were previously characterized using Sanger sequencing. The targeted capture NGS panel identified the SHM status of 34 of 35 CLL patients. We showed 100% sensitivity and specificity among the 33 CLL samples with both NGS and Sanger calls. Furthermore, we demonstrated that this panel can be combined with additional targeted capture panels to detect common and prognostically important CLL single nucleotide variants (SNV) and insertion/deletion (indel) variants as well as copy number variants (del17p). Thus, a targeted capture approach to IGHV SHM detection can be easily integrated into broader sequencing panels, allowing broad CLL prognostication in a single molecular assay.

  Study EGAS00001006887

• RNA isoform repertoire of neuropsychiatric risk genes in human brain

  Neuropsychiatric disorders are highly complex conditions and the risk of developing a disorder has been tied to hundreds of genomic variants that alter the expression and/or products (isoforms) made by risk genes. However, how these genes contribute to disease risk and onset through altered expression and RNA splicing is not well understood. Here we show our current understanding of gene isoforms is far from complete and reveal the precise splicing profiles of neuropsychiatric disorder risk genes. Combining our new bioinformatic pipeline IsoLamp with nanopore long-read amplicon sequencing, we deeply profiled the RNA isoform repertoire of 31 high-confidence neuropsychiatric disorder risk genes in human brain. We show most risk genes are more complex than previously reported, identifying 443 novel isoforms and 28 novel exons, including isoforms which alter protein domains, and genes such as ATG13 and GATAD2A where most expression was from previously undiscovered isoforms. The greatest isoform diversity was present in the schizophrenia risk gene ITIH4. Mass spectrometry of brain protein isolates confirmed translation of a novel exon skipping event in ITIH4, suggesting a new regulatory mechanism for this gene in brain. Our results emphasize the widespread presence of previously undetected RNA and protein isoforms in brain and provide an effective approach to address this knowledge gap. Uncovering the isoform repertoire of neuropsychiatric risk genes will underpin future analyses of the functional impact these isoforms have on neuropsychiatric disorders, enabling the translation of genomic findings into a pathophysiological understanding of disease.

  Study EGAS00001007744

• Discovery and validation of an ancillary genomic test of malignancy for primary melanocytic tumors

  Background:Pathological diagnosis of melanocytic tumors can be difficult and prone to error. More accurate and reliable ancillary investigations than those currently available are required to improve diagnostic accuracy. Goals: (1) to generate a genomic model for distinguishing benign (nevi) from malignant (melanoma) melanocytic skin tumors, developed from a customized gene panel evaluated on a cohort of 250 nevi and melanomas. (2) To evaluate the performance of the genomic model in melanocytic tumors of uncertain diagnosis/behavior. Details: The cohort of 250 melanomas and naevi was split into a discovery set and a validation set. Our genomic model obtained an area under the curve of 95% in the discovery cohort and 96% for the validation cohort. Based on a Youden index threshold, the resulting classifier shows high specificity (>95% in the discovery and validation cohorts), with sensitivities >80% in the discovery and validation cohorts. Evaluation of the genomic model on a cohort of 110 melanocytic tumors identifies key driver mutations in agreement with the likely pathway of origin of the tumors. The probability of melanoma (p=0.02) from the genomic model was significantly associated with pathology-based estimates of malignancy for melanocytic tumors lacking pathway-defining genomic aberrations (conventional tumors). The genomic model identified 8/36 (22%) conventional tumors with unresolved malignancy to have a high probability of melanoma, with 7/8 of these cases showing negative/non-aberrant results with either fluorescent in-situ hybridization, PRAME and/or p16 immunostains. Furthermore, no evidence of malignant behavior based on the genomic model was seen in 4 conventional borderline tumors with more than 1 year follow-up. Conclusion: This genomic model can become a clinically useful ancillary tool that is highly specific for differentiating melanomas from nevi.

  Study EGAS50000000887

• 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

• 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

• Molecular Genetics of Heterotaxy and Related Congenital Heart Defects

  Heterotaxy syndrome is a congenital anomaly syndrome accompanied by thoracic and abdominal situs abnormalities. The study cohort comprises of individuals with heterotaxy or related congenital heart disease (CHD) who have undergone exome sequencing. The purpose of the study is to elucidate the molecular genetics of the disorder as well as contribute to knowledge about the biology of normal and abnormal development of left-right anatomic asymmetry. These results will further help delineate genotype-phenotype associations and provide important information on the causes, management, and prognosis of heterotaxy syndrome.

  Study phs001814

• Diversity of the immune microenvironment and response to checkpoint inhibitor immunotherapy in mucosal melanoma

  Mucosal melanoma (MucM) is a rare cancer with a poor prognosis and low response rate to immune checkpoint inhibition (ICI) compared to cutaneous melanoma (CM). To explore the immune microenvironment and potential drivers of MucM’s relative resistance to ICI drugs, we characterized 101 MucM tumors (43 head and neck, 31 female urogenital, 13 male urogenital, 11 anorectal, and 3 other gastro-intestinal) using bulk RNA-sequencing (RNAseq). The original publication is written by JL Vos, JJH Traets, et al. and published in JCI Insight in 2024.

  Study EGAS50000000631

• High Resolution Analysis of Spatial Interactions of Hundreds of Promoters in HeLa Cells

  In this study we developed a new hybridisation-based promoter Capture-C protocol that makes use of biotinylated dsDNA probes and allows high-resolution promoter interactome description. Experiments aimed to describe spatial interactions of set of 861 promoters were performed in HeLa cells. We have found that enrichment efficiency and quality of final libraries in our study is on a par with established promoter Capture-C protocols. Meanwhile, our version of the probe preparation protocol is reasonably simple and makes Capture-C experiments more affordable and flexible.

  Study phs002014