Genomic variations associated with risk and protection against vincristine-induced peripheral neuropathy in pediatric cancer patients.

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2024-11-05 DOI:10.1038/s41525-024-00443-7
Kheireddin Mufti, Miguel Cordova, Erika N Scott, Jessica N Trueman, Jessica M Lovnicki, Catrina M Loucks, Shahrad R Rassekh, Colin J D Ross, Bruce C Carleton
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Abstract

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10-8) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).

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与小儿癌症患者中长春新碱诱发周围神经病变的风险和保护相关的基因组变异。
长春新碱诱发的周围神经病变是长春新碱治疗中一种常见且极易使人衰弱的毒性反应,会影响患者的生活质量,通常需要减少剂量,并可能影响患者的生存。尽管之前的研究表明遗传因素与长春新碱神经病变风险有关,但由于样本量小、临床表型不明确,大多数已确定变异的临床相关性受到限制。一项全基因组关联研究对 1100 例病例和对照组进行了长春新碱剂量和基因血统匹配,发现了 MCM3AP 基因中一个具有统计学意义(p -8)的变异,该变异会大大增加神经病变的风险,同时还发现了 SPDYA、METTL8、PDE4D、FBN2、ZFAND3、NFIB、PAPPA、LRRTM3、NRG3、VTI1A、ARHGAP5 和 ACTN1 基因内/附近的 12 个保护神经病变的变异。后续的通路分析显示,神经结构和发育、髓鞘化、神经元传导和细胞骨架/微纤维功能通路等四条关键通路参与其中。这些发现为长春新碱神经病变提供了潜在的可操作基因组标记,并为采取有针对性的干预措施以提高癌症患儿的长春新碱安全性提供了机会。该研究已在ClinicalTrials.gov网站注册,标题为 "国家主动监测网络和儿童药物不良反应药物基因组学"(ID NCT00414115,2006年12月21日注册)。
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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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