Duplication of the genome prior to cell division occurs in a spatially and temporally organized manner. The temporal order of replication (replication timing) reflects the higher order organization of the genome. During the first half of the S-phase, euchromatic regions are replicated followed by facultative heterochromatin during mid S-phase and finally constitutive heterochromatin regions in the second half of the S-phase. In the nucleus, euchromatin is localized in the interior while constitutive heterochromatin is rather located at the periphery. The spatio-temporal program of genome replication changes throughout development and cellular differentiation and has been correlated with changes in chromatin dynamics, histone marks, and nuclear architecture indicating that genome reorganization is associated with epigenetic and gene expression changes. Abnormal replication timing has also been reported in many diseases, including cancer. A growing body of evidence indicates that the replication-timing program strongly influences the spatial distribution of mutagenic events such that certain regions of the genome that are replicated in late S-phase present increased spontaneous mutagenesis compared to surrounding regions replicated in early S-phase. This has been observed during the evolution of species as well as during the evolution of cancer. In addition, a recent report showed that the dominant determinant of regional mutation rate variation is chromatin organization, with mutation rates elevated in more heterochromatin-like domains and repressed in more open chromatin. Although different hypotheses have been advanced, the cause of this increasing gradient of point mutation rates with later replication timing and the underlying mechanisms remain elusive. Although no mutagenic profile has been reported so far from pluripotent cells undergoing differentiation, one can expect that genome reorganization influences the mutagenic landscape. Obvious and important questions emerge from these observations: how and why elevated mutation rates are associated with heterochromatin-like domains which are replicated in late S-phase? What can be the “cost” for the cell when global genome reorganization takes place after differentiation/dedifferentiation (e.g. pre-cancerous cells) or reprogramming (e.g. iPS cells) if late-replicating regions containing point mutations become early and are actively transcribed? Point mutations arising in the genome are mainly caused by a special class of DNA polymerases (TLS polymerases) that support replication directly past template lesions (or unusual DNA secondary structures) that cannot be negotiated by the replicative high-fidelity polymerases. However, these specialized polymerases can be highly error-prone on undamaged DNA. An emerging concept proposes that these enzymes may also function during the unchallenged S-phase. On the basis of solid preliminary results, we assume that the essential error-prone DNA polymerase zeta (Pol zeta) is required to replicate through condensed chromatin regions and could be involved in the gradient of spontaneous mutagenesis. Therefore, this ambitious SPUR project aims to decipher the involvement of Pol zeta??and its catalytic subunit Rev3) in the regulation of the spatio-temporal program of DNA replication during embryonic stem cell differentiation and comprehensively evaluate the role of this error-prone polymerase in the point mutation frequencies which increase in late-replicating regions.

STRONG-AYA is a new, interdisciplinary, multi-stakeholder European network to improve healthcare services, research and outcomes for Adolescents and Young Adults (AYA) with cancer, defined as individuals aged 15-39 years at cancer diagnosis. AYAs with cancer form a unique group; they face age-specific issues (e.g. infertility, unemployment, financial problems) and decreased quality of life due to cancer and its treatment. Unlike dedicated healthcare and trials for pediatric cancer patients, AYA-specific healthcare services are scarce and vary across Europe. AYAs who are at the core of society and economy need access to age-adjusted and high-quality healthcare. AYA-care and research will benefit from collection and pooling of patient-centered data and collaboration among all stakeholders: patients, healthcare professionals, scientists, and policymakers. Our consortium of clinical and scientific leaders in AYA-care, data science and registries, European Cancer Organisation, Youth Cancer Europe and EORTC will build on previous initiatives and EU grants. Within STRONG-AYA we will set up a value-based healthcare research ecosystem to develop data-driven, interactive policy and visualization tools that bring, in co-creation with all stakeholders including patients, novel insights into AYA healthcare. The project objectives, include: 1) Development of a Core Outcome Set (COS) for AYAs with cancer; 2) Implementation of the COS in 5 national healthcare systems (FR, IT, NL, UK, PL) and establish national infrastructures for outcome data management and clinical decision-making and a pan-European ecosystem that also welcomes future European countries; 3) Disseminate outcomes and facilitate interactions between national and pan-European stakeholders to develop data-driven analysis tools to process and present relevant outcomes, establish feedback loops for AYA cancer patients and the healthcare systems, and improve the reporting and assessment of outputs towards policy-makers.

This translational and industrial program aims at positioning an innovative immunmodulatory agent, an improved and recombinant fusion IL-15 protein called CYP0150, to treat cancers in the best conditions. Based on a strong basis of relevant in vivo models (human immune system mouse, primates) and ex vivo tumor biopsies, we intend to validate the toxicology/pharmacology/immunogenicity ratio of this new drug to consolidate our regulatory preclinical studies. Moreover, thanks to many emerging and revolutionary concepts demonstrating the critical role of the immune system on the efficacy of many anticancer drug classes, several therapy combinations will be evaluated to leverage the pharmacological effects of RLI as best as possible and to define the best treatment combinations to be used in phase II clinical trials. Last but not least, specific molecules related to the IL-15/IL-15Ralpha transpresentation system will be monitored in cancer patient samples before and after therapy to define a relevant biomarker useful to predict and select the best-responsive patient populations for a CYP0150-based therapy as stand-alone or in combination with other anticancer drug classes. Based on the internal regulatory preclinical development of CYP0150 and this translational collaborative program, we should be able to initiate our clinical trials in cancer patients by early-2013 in optimal conditions and to consolidate our worldwide leadership position in this IL-15-related field.