Development of a somatic variant registry in a National Cancer Center: towards Molecular Real World Data preparedness.

The Biomedical Research field is currently advancing to develop Clinical Trials and translational projects based on Real World Evidence. To make this transition feasible, clinical centers need to work toward Data Accessibility and Interoperability. This task is particularly challenging when applied to Genomics, that entered in routinary screening in the last years via mostly amplicon-based Next-Generation Sequencing panels. Said experiments produce up to hundreds of features per patient, and their summarized results are often stored in static clinical reports, making critical information inaccessible to automated access and Federated Search consortia. In this study, we present a reanalysis of 4620 solid tumor sequencing samples in five different histology settings. Furthermore, we describe all the Bioinformatics and Data Engineering processes that were put in place in order to create a Somatic Variant Registry able to deal with the large biotechnological variability of routinary Genomics Profiling.

Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells.

Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem-like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors.