Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, Birmingham, AL.
Population Sciences, City of Hope, Duarte, CA.
J Clin Oncol. 2020 Apr 20;38(12):1312-1321. doi: 10.1200/JCO.19.01085. Epub 2020 Feb 21.
Using a candidate gene approach, we tested the hypothesis that individual single nucleotide polymorphisms (SNPs) and gene-level variants are associated with cognitive impairment in patients with hematologic malignancies treated with blood or marrow transplantation (BMT) and that inclusion of these SNPs improves risk prediction beyond that offered by clinical and demographic characteristics.
In the discovery cohort, BMT recipients underwent a standardized battery of neuropsychological tests pre-BMT and at 6 months, 1 year, 2 years, and 3 years post-BMT. Associations between 68 candidate genes and cognitive impairment were assessed using generalized estimating equation models. Elastic-Net regression was used to build Base (sociodemographic), Clinical, and Combined (Base plus Clinical plus genetic) risk prediction models of post-BMT impairment. An independent nonoverlapping cohort from the BMT Survivor Study with self-report of learning/memory problems (as identified by their health care provider) was used for model replication.
The discovery cohort included 277 participants (58.5% males; 68.6% non-Hispanic whites; and 46.6% allogeneic BMT recipients). Adjusting for BMT type, age at BMT, sex, race/ethnicity, and cognitive reserve, SNPs in the blood-brain barrier, telomere homeostasis, and DNA repair genes were significantly associated with cognitive impairment. Compared with the Clinical Model, the Combined Model had higher predictive power in both the discovery cohort (mean area under the receiver operating characteristic curve [AUC], 0.89; 95% CI, 0.85 to 0.93 0.77; 95% CI, 0.71 to 0.83; = 1.24 × 10) and the replication cohort (AUC, 0.71; 95% CI, 0.66 to 0.76 0.63; 95% CI, 0.57 to 0.68; = .004).
Inclusion of candidate genetic variants enhanced the prediction of risk of post-BMT cognitive impairment beyond that offered by demographic/clinical characteristics and represents a step toward a personalized approach to managing patients at high risk for cognitive impairment after BMT.
采用候选基因方法，我们检验了以下假设，即个体单核苷酸多态性（SNP）和基因水平变异与接受血液或骨髓移植（BMT）治疗的血液系统恶性肿瘤患者的认知障碍相关，并且包含这些 SNP 可以提高风险预测，超过临床和人口统计学特征提供的预测。
在发现队列中，BMT 受者在 BMT 前、BMT 后 6 个月、1 年、2 年和 3 年接受了标准化的神经心理学测试。使用广义估计方程模型评估 68 个候选基因与认知障碍的相关性。弹性网络回归用于构建 BMT 后损伤的基础（社会人口统计学）、临床和综合（基础加临床加遗传）风险预测模型。使用来自 BMT 幸存者研究的独立不重叠队列，其中自我报告有学习/记忆问题（由他们的医疗保健提供者确定），用于模型复制。
发现队列包括 277 名参与者（58.5%为男性；68.6%为非西班牙裔白人；46.6%为异基因 BMT 受者）。调整 BMT 类型、BMT 年龄、性别、种族/民族和认知储备后，血脑屏障、端粒稳态和 DNA 修复基因中的 SNP 与认知障碍显著相关。与临床模型相比，综合模型在发现队列（平均接收者操作特征曲线下面积[AUC]，0.89；95%CI，0.85 至 0.93 vs. 0.77；95%CI，0.71 至 0.83；=1.24×10）和复制队列（AUC，0.71；95%CI，0.66 至 0.76 vs. 0.63；95%CI，0.57 至 0.68；=0.004）中均具有更高的预测能力。
候选遗传变异的纳入增强了对 BMT 后认知障碍风险的预测，超过了人口统计学/临床特征提供的预测，代表了朝着为 BMT 后认知障碍风险高的患者实施个性化管理的方向迈出了一步。
