Mufti Kheireddin, Cordova Miguel, Scott Erika N, Trueman Jessica N, Lovnicki Jessica M, Loucks Catrina M, Rassekh Shahrad R, Ross Colin J D, Carleton Bruce C
Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
NPJ Genom Med. 2024 Nov 5;9(1):56. doi: 10.1038/s41525-024-00443-7.
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) 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).
长春新碱引起的周围神经病变是长春新碱治疗常见且极具致残性的毒性反应，会影响生活质量，常需减少剂量，这可能会影响生存期。尽管先前的研究表明遗传因素与长春新碱神经病变风险相关，但大多数已鉴定变异的临床相关性因样本量小和临床表型不明确而受限。在1100例病例和对照中开展了一项全基因组关联研究，这些病例和对照按长春新碱剂量和遗传血统进行匹配，发现MCM3AP基因中有一个具有统计学意义（p < 5.0 × 10）的变异，该变异大幅增加了神经病变风险，并且在SPDYA、METTL8、PDE4D、FBN2、ZFAND3、NFIB、PAPPA、LRRTM3、NRG3、VTI1A、ARHGAP5和ACTN1基因内部或附近发现了12个预防神经病变的变异。一项后续通路分析揭示了四个关键通路的参与，包括神经结构与发育、髓鞘形成、神经传递以及细胞骨架/微原纤维功能通路。这些发现提供了长春新碱神经病变潜在的可采取行动的基因组标记，并为采取针对性干预措施以提高癌症患儿长春新碱治疗的安全性提供了机会。本研究已在ClinicalTrials.gov上注册，标题为“国家儿童药物不良反应主动监测网络与药物基因组学”（标识符NCT00414115，于2006年12月21日注册）。
