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Approved Research

Exploring the impact of mutational burden on molecular traits and cancer risk

Principal Investigator: Dr Balázs Papp
Approved Research ID: 96168
Approval date: March 9th 2023

Lay summary

Mutations that strongly damage protein coding genes are typically eliminated by natural selection and therefore any such specific mutation is present at a very low frequency in the human population. Yet, each human individual carries several such damaging genetic variants and therefore their combined effects might be key determinants of human health. Indeed, increasing evidence shows that the combined germline burden of rare gene damaging contributes to various complex diseases and decreases lifespan as well as reproductive success in humans. However, it is poorly understood how the cumulative burden of such variants (i.e. mutational burden) shape key molecular traits, such as the concentrations of metabolites, and the risk of developing cancer. Studying the molecular impacts of high mutational burden would be important to better understand their clinical effects and to discover biomarkers that indicate if someone carries an excessive amount of damaging gene variants. Here we hypothesize that high mutational burden i)  induces common metabolic alterations that might be detectable even without manifested clinical signs and ii) increase the susceptibility to certain cancer types. To test the first hypothesis, we will seek recurrent metabolome signatures associated with high mutational burden in UK Biobank participants. The second hypothesis will be tested by examining the burden of rare variants in cancer patients and identifying enriched mutated gene classes that could explain the potential association between these variants and certain tumor types.