File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

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

TitleGanciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies.
Authors
KeywordsDNA damage
Ganciclovir
Mutagenesis
Mutational signature
Organ transplant
Issue Date31-Oct-2022
PublisherBioMed Central
Citation
Genome Medicine, 2022, v. 14, n. 1 How to Cite?
AbstractBACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nGanciclovir (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.\nThis 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 (GCVsig) 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.\nMutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. 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 GCVsig 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 GCVsig 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 GCVsig in cell lines and organoids.\nIn 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.
Persistent Identifierhttp://hdl.handle.net/10722/331404
ISSN
2023 Impact Factor: 10.4
2023 SCImago Journal Rankings: 4.975
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFang, H-
dc.contributor.authorYan, HHN-
dc.contributor.authorBilardi, RA-
dc.contributor.authorFlensburg, C-
dc.contributor.authorYang, H-
dc.contributor.authorBarbour, JA-
dc.contributor.authorSiu, HC-
dc.contributor.authorTurski, M-
dc.contributor.authorChew, E-
dc.contributor.authorXu, Z-
dc.contributor.authorLam, ST-
dc.contributor.authorSharma, R-
dc.contributor.authorXu, M-
dc.contributor.authorLi, J-
dc.contributor.authorIp, HW-
dc.contributor.authorCheung, CYM-
dc.contributor.authorHuen, MSY-
dc.contributor.authorSweet-Cordero, EA-
dc.contributor.authorMajewski, IJ-
dc.contributor.authorLeung, SY-
dc.contributor.authorWong, JWH-
dc.date.accessioned2023-09-21T06:55:24Z-
dc.date.available2023-09-21T06:55:24Z-
dc.date.issued2022-10-31-
dc.identifier.citationGenome Medicine, 2022, v. 14, n. 1-
dc.identifier.issn1756-994X-
dc.identifier.urihttp://hdl.handle.net/10722/331404-
dc.description.abstractBACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nGanciclovir (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.\nThis 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<sup>sig</sup>) 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.\nMutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCV<sup>sig</sup>. 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<sup>sig</sup> 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<sup>sig</sup> 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<sup>sig</sup> in cell lines and organoids.\nIn 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.-
dc.languageeng-
dc.publisherBioMed Central-
dc.relation.ispartofGenome Medicine-
dc.subjectDNA damage-
dc.subjectGanciclovir-
dc.subjectMutagenesis-
dc.subjectMutational signature-
dc.subjectOrgan transplant-
dc.titleGanciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies.-
dc.typeArticle-
dc.identifier.doi10.1186/s13073-022-01131-w-
dc.identifier.pmid36316687-
dc.identifier.scopuseid_2-s2.0-85140938528-
dc.identifier.volume14-
dc.identifier.issue1-
dc.identifier.eissn1756-994X-
dc.identifier.isiWOS:000877005400001-
dc.identifier.issnl1756-994X-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats