Mutational consequences of hematopoietic stem cell transplantation in humans

Genetic instability is a major concern for the successful application of stem cells in regenerative medicine. However, the mutational consequences of the most commonly applied stem cell therapy in humans, hematopoietic stem cell transplantation (HSCT), remain unknown. Here, we characterized by whole genome sequencing the genome-wide mutation burden of hematopoietic stem and progenitor cells (HSPCs) of human HSCT recipients and their donors. We demonstrate that the majority of transplanted HSPCs did not display altered mutation accumulation. However, in some HSCT recipients, we identified multiple HSPCs with increased mutation burden after transplantation. This increase could be attributed exclusively to a novel mutational signature, which reflects aberrant DNA replication. Using a machine-learning approach, we detected this signature in cancer genomes of patients who received HSCT or a solid organ transplantation earlier in life. Our results show that HSCT can be associated with enhanced mutagenicity, which may ultimately contribute to carcinogenesis.EGA study EGAS00001004926