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.

实体器官移植或造血干细胞移植（hematopoietic stem cell transplants, HSCT）受者罹患癌症的风险显著升高。既往研究认为，长期免疫抑制与病毒感染是移植术后恶性肿瘤风险升高的核心诱因。确实，硫唑嘌呤（azathioprine）等药物已被证实可造成DNA损伤，而移植受者感染爱泼斯坦-巴尔病毒（Epstein-Barr virus）这类致癌病毒的比例也显著更高。近期有研究报道，抗病毒药物更昔洛韦（ganciclovir, GCV）可诱导一种以CA>AA碱基替换为主的独特突变特征，该特征在造血干细胞移植后的血细胞祖细胞及部分癌症组织中均有体现。我们证实了更昔洛韦与该CA>AA突变特征之间的关联——这一关联此前我们曾在2名兼具急性髓系白血病、造血干细胞移植及结直肠癌病史的个体中观察到。通过对超过13万名患者的靶向测序数据进行分析，我们在约每8965例病例中即可发现1例存在与更昔洛韦暴露相关的突变证据。利用细胞系暴露模型，我们还发现更昔洛韦与免疫抑制剂吗替麦考酚酯（mycophenolate mofetil）之间存在潜在相互作用，这或可解释不同病例间突变负荷的部分差异。