Ganciclovir induces DNA damage that contributes to the elevated cancer risk after organ transplantation

Recipients of solid organ or hematopoietic stem cell transplants (HSCT) have a much higher risk of developing canceer. It has been assumed that long term immunosuppression and viral infection account for the elevated risk of post-transplant malignancy. Indeed, drugs such as azathioprine are known to damage DNA, and transplant recipients experience higher rates of infection with oncogenic viruses, such as Epstein-Barr virus. Recently, it was reported that the antiviral ganciclovir (GCV) induces a distinctive mutational signature, dominated by CA>AA substitutions, evident in blood cell progenitors after HSCT and in some cancers. We confirmed the link between GCV and the CA>AA signature, which we previously observed in two individuals with a shared history of acute myeloid leukaemia, HSCT and colorectal cancer. By interrogating targeted sequencing data from over 130,000 patients, we found evidence of mutations linked to GCV exposure in ~1 in 8,965 cases. Using cell line exposure models, we identified a potential interaction between GCV and the immunosuppressant mycophenolate mofetil, which may explain some variability in mutation burden between cases.