Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients.
Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients.
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DOI：
10.1016/j.stem.2021.07.012
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发表时间：
2021-10-07
期刊：
影响因子：
23.9
通讯作者：
van Boxtel R
中科院分区：
文献类型：
--
作者：
de Kanter JK;Peci F;Bertrums E;Rosendahl Huber A;van Leeuwen A;van Roosmalen MJ;Manders F;Verheul M;Oka R;Brandsma AM;Bierings M;Belderbos M;van Boxtel R
遗传不稳定性是影响干细胞在再生医学中成功应用的主要问题。然而，人类最常用的干细胞治疗——造血干细胞移植（HSCT）的突变后果仍然未知。在这里，我们使用全基因组测序技术表征了人类造血干细胞受体及其供者造血干细胞和祖细胞（HSPCs）的突变负担。我们证明，大多数移植的HSPCs没有表现出改变的突变积累。然而，在一些HSCT受者中，我们发现多个HSPCs在移植后突变负担增加。这种增加可能归因于抗病毒药物更昔洛韦引起的一种独特的突变特征。使用机器学习方法，我们在生命早期接受HSCT或实体器官移植的个体的癌症基因组中检测到这种特征。用核苷类似物进行抗病毒治疗可增强移植受者的突变性，这可能最终导致治疗相关的癌变。在移植的造血干细胞中，抗病毒药物更昔洛韦引起独特的突变特征。更昔洛韦相关的突变在移植受者的癌症中被发现。更昔洛韦可以引起移植受者癌症的遗传驱动因素。在治疗相关的癌症中也发现了这种特征，并可能导致癌症驱动突变。
Genetic instability is a major concern for successful application of stem cells in regenerative medicine. However, the mutational consequences of the most applied stem cell therapy in humans, hematopoietic stem cell transplantation (HSCT), remain unknown. Here we characterized the mutation burden of hematopoietic stem and progenitor cells (HSPCs) of human HSCT recipients and their donors using whole-genome sequencing. We demonstrate that the majority of transplanted HSPCs did not display altered mutation accumulation. However, in some HSCT recipients, we identified multiple HSPCs with an increased mutation burden after transplantation. This increase could be attributed to a unique mutational signature caused by the antiviral drug ganciclovir. Using a machine learning approach, we detected this signature in cancer genomes of individuals who received HSCT or solid organ transplantation earlier in life. Antiviral treatment with nucleoside analogs can cause enhanced mutagenicity in transplant recipients, which may ultimately contribute to therapy-related carcinogenesis. Stem cell transplantation does not enhance mutagenesis in most human recipients The antiviral drug ganciclovir causes unique mutation signature in transplanted HSPCs Ganciclovir-associated mutagenesis is found in cancers of transplantation recipients Genetic drivers in cancers of transplantation recipients can be caused by ganciclovir de Kanter et al. demonstrate that antiviral treatment with ganciclovir causes a unique mutational signature in stem cells of human transplant recipients. This signature was also found in therapy-related cancers and can cause cancer driver mutations.
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影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
正常细胞的基因组测序揭示了发育谱系和突变过程。
影响因子：
64.8
作者：
Behjati, Sam;Huch, Meritxell;van Boxtel, Ruben;Karthaus, Wouter;Wedge, David C.;Tamuri, Asif U.;Martincorena, Inigo;Petljak, Mia;Alexandrov, Ludmil B.;Gundem, Gunes;Tarpey, Patrick S.;Roerink, Sophie;Blokker, Joyce;Maddison, Mark;Mudie, Laura;Robinson, Ben;Nik-Zainal, Serena;Campbell, Peter;Goldman, Nick;van de Wetering, Marc;Cuppen, Edwin;Clevers, Hans;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
2.8
作者：
Bhatia S
通讯作者：
Bhatia S
影响因子：
20.3
作者：
Boettcher, Steffen;Wilk, C. Matthias;Manz, Markus G.
通讯作者：
Manz, Markus G.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y