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Health networking is in principle a formidable instrument to address many challenges posed by cancer, one of the two most common and most lethal non-communicable chronic diseases. The European Union (EU)'s Beating Cancer Plan foresaw the addition of new health networks to the four already existing European Reference Networks on rare cancers: the Network of Comprehensive Cancer Centres and several networks of expertise (NoEs), which will be shortly deployed on items as complex and poor-prognosis cancers, palliative care, survivorship, personalised primary and secondary prevention, omic technologies, hi-tech medical resources, and cancers in adolescents and young adults. The community of experts of the EU Joint Action, due to build such NoEs, has drafted this 'green paper', incorporating 13 open questions, in an effort to foster discussion on some open questions about health networking on cancer in the EU. These affect highly diverse issues such as the following: how gaps in research into the instrument of health networking may be filled; which items lend themselves more to health networking in the EU; what degree of cooperation and harmonisation should be required of EU member states to best exploit health networking and give rise to European networks of national/regional networks; how the idea of subsidiarity may be best interpreted to support health networking in the context of EU treaties, which basically do not include health; how health networks should be funded and with what degree of cooperation between the EU and national levels; whether EU health networks should be shaped as legal entities or could give rise to secondary legal entities, also with a view to fundraising; how health networks should be best shaped to advance cancer research and how the EU regulatory system should be updated to exploit such impulse to health networks, in view of the EU General Data Protection Regulation and the new EU Health Data Space; how artificial intelligence can be exploited today within health networks and to what extent it will be able to overcome challenges such as the current lack of interoperability of electronic health records and the language barrier across the EU; and how health networks should involve patients and their groups, with regard to their formal role within EU health networks as well as their ability to have a say in items such as production of clinical practice guidelines, the design of investigator-driven clinical trials, EU regulatory decisions on medicines and devices, health service data governance, and identification of unmet needs., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor that is critical for definitive hematopoiesis, stem cell function, and platelet maintenance. ERG colocalizes with other transcription factors, including RUNX family transcription factor 1 (RUNX1) and GATA binding protein 2 (GATA2), on promoters or enhancers of genes that orchestrate hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 individuals with thrombocytopenia from 1 family and 14 additional ERG variants in unrelated individuals with BMF/HM, including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germ line ERG variants included cytopenias (thrombocytopenia, neutropenia, and pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense and 1 truncating), including 3 missense population variants, were functionally characterized. Thirteen potentially pathogenic erythroblast transformation specific (ETS) domain missense variants displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture and to promote acute erythroleukemia when transplanted into mice, concordant with these being LOF variants. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germ line ERG variants has clinical implications for patient and family diagnoses, counseling, surveillance, and treatment strategies, including selection of bone marrow donors and cell or gene therapy., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.