儿童癌症治疗长期不良反应的遗传和表观遗传学基础-动脉网

Genetic and epigenetic bases of long-term adverse effects of childhood cancer therapy

Nature 等信源发布 2024-11-07 05:29

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AbstractOver the past decade, genome-scale molecular profiling of large childhood cancer survivorship cohorts has led to unprecedented advances in our understanding of the genetic and epigenetic bases of therapy-related adverse health outcomes in this vulnerable population. To facilitate the integration of knowledge generated from these studies into formulating next-generation precision care for survivors of childhood cancer, we summarize key findings of genetic and epigenetic association studies of long-term therapy-related adverse effects including subsequent neoplasms and cardiomyopathies among others.

摘要在过去的十年中，大型儿童癌症幸存者队列的基因组规模分子谱分析使我们对这一弱势人群中与治疗相关的不良健康结果的遗传和表观遗传基础的理解取得了前所未有的进展。为了促进将这些研究产生的知识整合到为儿童癌症幸存者制定下一代精准护理中，我们总结了长期治疗相关不良反应（包括随后的肿瘤和心肌病等）的遗传和表观遗传关联研究的关键发现。

We also discuss therapy-related genotoxicities including clonal haematopoiesis and DNA methylation, which may underlie accelerated molecular ageing. Finally, we highlight enhanced risk prediction models for survivors of childhood cancer that incorporate both genetic factors and treatment exposures, aiming to achieve enhanced accuracy in predicting risks for this population.

我们还讨论了与治疗相关的基因毒性，包括克隆造血和DNA甲基化，这可能是加速分子衰老的基础。最后，我们重点介绍了儿童癌症幸存者的增强风险预测模型，该模型结合了遗传因素和治疗暴露，旨在提高预测该人群风险的准确性。

These new insights will hopefully inspire future studies that harness both expanding omics resources and evolving data science methodology to accelerate the translation of precision medicine for survivors of childhood cancer..

这些新的见解有望激发未来的研究，利用不断扩大的组学资源和不断发展的数据科学方法，加速为儿童癌症幸存者翻译精准医学。。

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Access Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription24,99 € / 30 dayscancel any timeLearn moreSubscription info for Chinese customersWe have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.Go to naturechina.comBuy this articlePurchase on SpringerLinkInstant access to full article PDFBuy nowPrices may be subject to local taxes which are calculated during checkout.

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Fig. 1: Genetic contributions to adverse late effects in survivors of childhood cancer.Fig. 2: Established host genetic risk factors and their implicated biological pathways for subsequent breast cancer, subsequent thyroid cancer and cardiomyopathy among survivors of childhood cancer.Fig. 3: Interactions between ageing biomarkers, risk factors and chronic health conditions.Fig.

图1：对儿童癌症幸存者不良晚期影响的遗传贡献。图2：儿童癌症幸存者中确定的宿主遗传危险因素及其与随后的乳腺癌，随后的甲状腺癌和心肌病有关的生物学途径。图3：衰老生物标志物，危险因素和慢性健康状况之间的相互作用。图。

4: A scheme for future research into cancer survivorship..

4：未来癌症幸存者研究计划。。

Data availability

数据可用性

Previously published data were used for plotting graphs in Figs. 1 and 3. Details can be found in each of the corresponding figure legends.

先前发布的数据用于绘制图1和图3中的图形。详细信息可以在每个相应的图例中找到。

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Download referencesAcknowledgementsThe authors thank L. Robison, G. Armstrong, C. Im, J. Klco and Y. Sapkota for help in reviewing and providing critical feedback on the manuscript. They thank Q. Dong, K. Hagiwara, X. Meng and N. Plonski for helping with preparation of figures and tables.

下载参考文献致谢作者感谢L.Robison，G.Armstrong，C.Im，J.Klco和Y.Sapkota在审阅稿件和提供批判性反馈方面的帮助。他们感谢Q.Dong、K.Hagiwara、X.Meng和N.Plonski帮助编制图表。

This study was supported, in part, by National Cancer Institute (NCI) grants R01CA216391 to J.Z. and R01CA290112, R01CA279520 and R01CA283333 to Z.W. The study is also supported by American Lebanese Syrian Associated Charities (ALSAC).Author informationAuthors and AffiliationsDepartment of Epidemiology and Cancer Control, St.

这项研究得到了国家癌症研究所（NCI）向J.Z.授予R01CA216391，向Z.W授予R01CA290112，R01CA279520和R01CA28333的部分支持。这项研究也得到了美国黎巴嫩叙利亚联合慈善机构（ALSAC）的支持。。

Jude Children’s Research Hospital, Memphis, TN, USAZhaoming WangDepartment of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USAZhaoming Wang & Jinghui ZhangAuthorsZhaoming WangView author publicationsYou can also search for this author in.

美国田纳西州孟菲斯裘德儿童研究医院王兆明美国田纳西州孟菲斯圣裘德儿童研究医院计算生物学系王兆明和张景辉作者王兆明观点作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarJinghui ZhangView author publicationsYou can also search for this author in

PubMed谷歌学者张景辉查看作者出版物您也可以在

PubMed Google ScholarContributionsThe authors contributed equally to all aspects of the article.Corresponding authorsCorrespondence to

PubMed谷歌学术贡献作者对文章的各个方面都做出了同样的贡献。通讯作者通讯

Zhaoming Wang or Jinghui Zhang.Ethics declarations

王兆明或张景辉。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Peer review

同行评审

Peer review information

同行评审信息

Nature Reviews Cancer thanks Jaume Mora, Javid Moslehi and Ruben van Boxtel for their contribution to the peer review of this work.

《自然评论》癌症感谢Jaume Mora，Javid Moslehi和Ruben van Boxtel为这项工作的同行评审做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Related linksALTE03N1: https://clinicaltrials.gov/study/NCT00082745dbGaP: https://dbgap.ncbi.nlm.nih.govEuropean Genome–Phenome Archive (EGA): https://ega-archive.org/Onco-Aging Consortium (OAC): https://www.cancer.gov/about-nci/organization/dcb/research-programs/oacSt.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。相关链接Salte03N1：https://clinicaltrials.gov/study/NCT00082745dbGaP:（笑声）https://dbgap.ncbi.nlm.nih.govEuropean基因组-现象组档案（EGA）：https://ega-archive.org/Onco-Aging联合体（OAC）：https://www.cancer.gov/about-nci/organization/dcb/research-programs/oacSt.

Jude Cloud: https://platform.stjude.cloudSt. Jude Survivorship Portal: https://viz.stjude.cloud/cancer-survivorship/visualization/st-jude-survivorship-portal~18The Surveillance, Epidemiology, and End Results (SEER) Program: https://seer.cancer.gov/GlossaryArea deprivation index.

https://platform.stjude.cloudSt.Jude Survivorship门户：https://viz.stjude.cloud/cancer-survivorship/visualization/st-jude-survivorship-portal约18监测、流行病学和最终结果（SEER）计划：https://seer.cancer.gov/GlossaryArea剥夺指数。

A multidimensional evaluation of socio-economic conditions for a geographical region.

。

Cardiomyopathy

心肌病

A disease that affects the heart muscle, making it difficult for the heart to pump blood to the rest of the body.

一种影响心肌的疾病，使心脏难以将血液泵送到身体的其他部位。

Clonal haematopoiesis

克隆造血

(CH). A condition that is characterized by the outsized contribution of expanded clones of haematopoietic stem and progenitor cells (HSPCs) to blood cell production.

（CH）。一种以造血干细胞和祖细胞（HSPC）扩增克隆对血细胞产生的巨大贡献为特征的疾病。

Effect sizes

效果大小

Quantitative measurements of the magnitude of a difference or association between variables.

变量之间差异或关联程度的定量测量。

Epigenetic clocks

表观遗传钟

Tools that measure biological age based on DNA methylation patterns.

基于DNA甲基化模式测量生物年龄的工具。

Expression quantitative trait locus

表达数量性状基因座

A genetic variant that affects the expression of one or more genes.

影响一个或多个基因表达的遗传变异。

Genome-wide association studies

全基因组关联研究

(GWAS). A research method that compares the genomes of many people to identify genetic markers associated with a disease or trait.

（GWAS）。。

Genotoxicities

基因毒性

The ability of a chemical or physical agent to damage a cell’s DNA, which can lead to mutations and modifications.

化学或物理因素破坏细胞DNA的能力，这可能导致突变和修饰。

Haplotype

单倍型

A group of genetic variants on a single chromosome that are inherited from the same parent.

从同一亲本遗传的单个染色体上的一组遗传变异。

Hypercholesterolaemia

高胆固醇血症

A condition with abnormally high levels of cholesterol in the blood.

血液中胆固醇含量异常高的病症。

Hypertriglyceridaemia

高甘油三酯血症

A condition with abnormally high levels of triglycerides (TGs) in the blood.

血液中甘油三酯（TGs）含量异常高的病症。

Minor allele frequency

次等位基因频率

(MAF). The frequency at which the less common allele (that is, the ‘minor allele’) occurs within a specific population.

（MAF）。不太常见的等位基因（即“次要等位基因”）在特定人群中出现的频率。

Myopenia

肌肉减少

A substantial amount of muscle loss.

大量肌肉损失。

Odds ratio

优势比

A statistical measurement that shows how strongly an event is associated with an exposure.

一种统计测量，显示事件与暴露的关联程度。

Ototoxic effects

耳毒性作用

Damage to the inner ear that can cause hearing or balance problems.

内耳受损，可能导致听力或平衡问题。

Outcome ascertainment

结果确定

A process of identifying and classifying relevant events (for example, diseases).

。

Sarcopenia

肌肉减少症

A condition characterized by loss of muscle mass, strength and function.

以肌肉质量、力量和功能丧失为特征的疾病。

Single nucleotide polymorphism

(SNP). A variant in a DNA sequence where a single nucleotide is different from the reference sequence.

（SNP）。DNA序列中的变体，其中单个核苷酸与参考序列不同。

Splicing quantitative trait locus

剪接数量性状基因座

A genetic variant that regulates how pre-mRNA for a gene is spliced.

调节基因前体mRNA剪接方式的遗传变异。

Trans-ancestral replication

跨祖先复制

A method for identifying genetic risk variants across different ancestries.

一种识别不同祖先遗传风险变异的方法。

Variant allele fraction

变异等位基因分数

(VAF). A measure of the proportion of variant alleles in a genetic locus by dividing the number of sequence reads harbouring a specific variant by the total number of reads at that genomic location.

（VAF）。通过将携带特定变体的序列读数除以该基因组位置的读数总数来衡量遗传基因座中变异等位基因的比例。

Rights and permissionsSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsAbout this articleCite this articleWang, Z., Zhang, J.

权利和许可Pringer Nature或其许可人（例如协会或其他合作伙伴）根据与作者或其他权利持有人的出版协议对本文拥有专有权；本文接受稿件版本的作者自行存档仅受此类出版协议和适用法律的条款管辖。转载和许可本文引用本文Wang，Z.，Zhang，J。

Genetic and epigenetic bases of long-term adverse effects of childhood cancer therapy..

儿童癌症治疗长期不良反应的遗传和表观遗传基础。。

Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00768-6Download citationAccepted: 01 October 2024Published: 07 November 2024DOI: https://doi.org/10.1038/s41568-024-00768-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Nat Rev Cancer（2024）。https://doi.org/10.1038/s41568-024-00768-6Download引文接受日期：2024年10月1日发布日期：2024年11月7日OI：https://doi.org/10.1038/s41568-024-00768-6Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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