Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies

Fang, H; Yan, HHN; Bilardi, RA; Flensburg, C; Yang, H; Barbour, JA; Siu, HC; Turski, M; Chew, E; Xu, Z; Lam, ST; Sharma, R; Xu, M; Li, J; Ip, HW; Cheung, CYM; Huen, MSY; Sweet-Cordero, EA; Majewski, IJ; Leung, SY; Wong, JWH

Author(s): Fang, H; Yan, HHN; Bilardi, RA; Flensburg, C; Yang, H; Barbour, JA; Siu, HC; Turski, M; Chew, E; Xu, Z; Lam, ST; Sharma, R; Xu, M; Li, J; Ip, HW; Cheung, CYM; Huen, MSY; Sweet-Cordero, EA; Majewski, IJ; Leung, SY; Wong, JWH;
Details: Publication Year 2022-10-31,Volume 14,Issue #1,Page 124
Journal Title: Genome Medicine
Abstract: BACKGROUND: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. METHODS: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCV(sig)) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. RESULTS: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCV(sig). A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCV(sig) were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV(sig) are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCV(sig) in cell lines and organoids. CONCLUSIONS: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.
Publisher: BMC
Keywords: Humans; Ganciclovir/pharmacology/therapeutic use; Cytomegalovirus Infections/drug therapy/prevention & control; Retrospective Studies; Antiviral Agents/adverse effects; Immunosuppressive Agents/adverse effects; Mutation; Neoplasms/genetics/drug therapy
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 36316687
Publisher's Version: https://doi.org/10.1186/s13073-022-01131-w
Open Access at Publisher's Site: https://doi.org/10.1186/s13073-022-01131-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Fang H et al_Genome Medicine_2022.pdf - (2.36MB, application/pdf)

Creation Date: 2022-11-08 02:27:10

Last Modified: 2022-12-05 07:50:09