Nucleoside analogue treatment post-transplant induces a novel mutation signature that can drive malignancy.
Major Finding: Nucleoside analogue treatment post-transplant induces a novel mutation signature that can drive malignancy.
Concept: Ganciclovir treatment was attributed to increased mutation burden through a distinct signature.
Impact: This work implicates ganciclovir in increased mutagenicity and malignant transformation in transplant recipients.
Hematopoietic stem cell transplantation (HSCT) is a common curative therapy used in the treatment of a wide range of diseases, including sickle cell anemia, bone marrow failure syndromes, and cancers such as leukemia. However, one key concern over the use of live cell therapy is the presence or development of DNA mutations, which can negatively affect efficacy or even lead to malignant transformation. The potential consequences that these mutations may have on patient safety remain unknown. Using whole-genome sequencing of hematopoietic stem and progenitor cells (HSPC), de Kanter, Peci, and colleagues investigated mutational burden in healthy donors and those having undergone HSCT and found that most HSCT recipients did not have any significant induction of mutagenesis. However, an exception was observed in two patients, in whom an increase in mutation burden was ascribed to C > A transversions at CpA dinucleotides. This signature, termed SBSA, was specifically observed in patients having undergone HSCT and subsequent antiviral treatment with the nucleoside analogue ganciclovir to treat viral reactivation. The induction of this unique signature through ganciclovir treatment was also confirmed by in vitro exposure of HSPCs from umbilical cord blood to ganciclovir. Furthermore, application of machine learning techniques showed that this unique mutagenic signature was present in both patients with hematologic malignancies who received HSCT and solid tumors of organ transplantation recipients, and the treatment history that was available for some of these patients indicated that they had received ganciclovir. Of note, driver mutations within these cancers, such as those in HRAS, NRAS, and SETBP1, were attributed to this particular signature. This work provides evidence of increased mutagenicity in transplanted HSPCs following treatment with nucleoside analogues such as ganciclovir. Moreover, it suggests that treatment with this type of therapeutic can contribute to development of malignancies and their driver mutations, supporting the use of alternative, nonmutagenic antivirals for this population.
de Kanter JK, Peci F, Bertrums E, Rosendahl Huber A, van Leeuwen A, van Roosmalen MJ, et al. Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients. Cell Stem Cell 2021 Sep 7 [Epub ahead of print].
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