Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.
Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.
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小儿急性淋巴细胞白血病治疗期间与疲劳相关的脑脊液代谢组学特征
DOI：
10.1016/j.jpainsymman.2020.08.030
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发表时间：
2021-03
影响因子：
4.7
通讯作者：
Scheurer ME
中科院分区：
文献类型：
--
作者：
Brown AL;Sok P;Taylor O;Woodhouse JP;Bernhardt MB;Raghubar KP;Kahalley LS;Lupo PJ;Hockenberry MJ;Scheurer ME
癌症相关疲劳（CRF）是儿童急性淋巴细胞白血病（ALL）治疗期间报告的最令人痛苦且持续存在的症状之一；然而，关于CRF严重程度潜在途径的信息有限。因此，我们对脑脊液（CSF）样本进行了全面的代谢组学分析，以深入了解CRF的潜在机制。
在2012 - 2017年期间，对儿童ALL患者在诱导治疗后（诊断后约6个月）进行了疲劳评估。收集了171名参与者的诱导治疗后CSF，包括发现队列（n = 86）和验证队列（n = 85）。我们还使用来自48名验证队列参与者的诊断时CSF进行了二次验证。使用气相色谱 - 质谱（MS）和液相色谱 - MS/MS对CSF进行代谢组学分析。采用肯德尔等级相关来评估代谢物丰度与CRF之间的关联。使用错误发现率（FDR）来处理多重比较。
参与者中56%为男性，59%为西班牙裔，诊断时的平均年龄为8.5岁。发现队列和验证队列共有274种来自CSF的代谢物。在发现队列中有8种代谢物与疲劳显著相关（p < 0.05），其中3种在验证队列中也显著相关，包括与γ - 谷氨酰谷氨酰胺（综合p = 6.2E - 6）和天冬酰胺（综合p = 3.5E - 4）经FDR校正后的关联。值得注意的是，诊断时CSF样本中γ - 谷氨酰谷氨酰胺的丰度也与疲劳显著相关（p = 0.0062）。
我们评估中确定的代谢物与神经递质运输和谷胱甘肽循环有关，这表明谷氨酸能途径或氧化应激可能导致与ALL相关的CRF。这一信息可为高危个体减少CRF的靶向治疗提供依据。
Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited. Therefore, we conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF. Fatigue in pediatric ALL patients (2012–2017) was assessed during post-induction therapy approximately 6-months post-diagnosis. Post-induction CSF was collected on 171 participants, comprising discovery (n=86) and replication (n=85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall’s rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate (FDR) was used to account for multiple comparisons. Participants were 56% male and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (p<0.05), of which three were significant in the replication cohort, including FDR-corrected associations with gamma-glutamylglutamine (pcombined = 6.2E-6) and asparagine (pcombined = 3.5E-4). Notably, the abundance of gamma-glutamylglutamine in diagnostic CSF samples was also significantly associated with fatigue (p=0.0062). The metabolites identified in our assessment have been implicated in neurotransmitter transportation and glutathione recycling, suggesting glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF. This information could inform targeted therapies for reducing CRF in at-risk individuals.
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