ELEGANT NORTH

In this project, we aim to study genomic alterations found in children with cancer, focusing mainly on leukemia cancer types, as a prototype of a rare disease. Rare diseases are life-threatening or severely debilitating and occur in fewer individuals, most of which are caused by known genetic alterations. The challenge, especially in the case of cancer, is that two patients with the same rare disease may have different course of the disease due to other variants in their genome that are poorly investigated.

ELEGANT NORTH provides access to transnational genomic and clinical data in the Nordic Countries to increase the number of cases that can be analyzed for a specific rare disease that can be used for the research. In particular, we are interested in applying and further developing a computational framework for variant interpretation developed in our group, i.e. MAVISp,  to understand the mechanisms of action of variants found in the cohorts of patients provided by ELEGANT NORTH.

We will re-analyze pre-collected and curated data from whole genome sequencing or targeted sequencing from the hospital cohorts to prioritize poorly investigated genes and their mutations for structural studies. The framework includes a variety of computational methods based on molecular modelling and simulations to associate the corresponding functional effects to protein mutations and support the identification of the suitable experimental design for validation, for example, for proteins involved in cell death, proliferation or DNA repair.

Additionally, the analyses with the framework will generate a group of features that can be combined with the clinical data on the patient history and therapy response using machine learning approaches, which can shed light on the different patients’ outcomes, along with identifying new targetable mutations or mutations that are associated with predisposition to childhood cancer. Additionally, the most interesting mutations identified by the screening in silico will be validated experimentally using cellular models for acute lymphoblastic or myeloid leukemia with cellular assays to study the effects of the mutations on protein levels, interactions and biological readouts correlated to cancer progression (such as changes in cell proliferation, migration, DNA repair, cell death).

The project is partially funded by the European Regional Development Fund and Interreg Öresund–Kattegat–Skagerrak.