DataSheet1_The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis.pdf

Objective: High-dose methotrexate (HDMTX) is a mainstay therapeutic agent for the treatment of diverse hematological malignancies, and it plays a significant role in interindividual variability regarding the pharmacokinetics and toxicity. The genetic association of HDMTX has been widely investigated, but the conflicting results have complicated the clinical utility. Therefore, this systematic review aims to determine the role of gene variants within the HDMTX pathway and to fill the gap between knowledge and clinical practice.
Methods: Databases including EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Clinical Trials.gov were searched from inception to November 2020. We included twelve single-nucleotide polymorphisms (SNPs) within the HDMTX pathway, involving RFC1, SLCO1B1, ABCB1, FPGS, GGH, MTHFR, DHFR, TYMS, and ATIC. Meta-analysis was conducted by using Cochrane Collaboration Review Manager software 5.3. The odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were analyzed to evaluate the associations between SNPs and clinical outcomes. This study was performed according to the PRISMA guideline.
Results: In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving MTHFR, RFC1, ABCB1, SLCO1B1, TYMS, FPGS, and ATIC genes were investigated, while none of studies reported the polymorphisms of GGH and DHFR yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: MTHFR 677C>T and hepatotoxicity (dominant, OR=1.52, 95% CI=1.03-2.23; recessive, OR=1.68, 95% CI=1.10–2.55; allelic, OR=1.41, 95% CI=1.01–1.97), mucositis (dominant, OR=2.11, 95% CI=1.31–3.41; allelic, OR=1.91, 95% CI=1.28–2.85), and renal toxicity (recessive, OR=3.54, 95% CI=1.81–6.90; allelic, OR=1.89, 95% CI=1.18–3.02); ABCB1 3435C>T and hepatotoxicity (dominant, OR=3.80, 95% CI=1.68-8.61), whereas a tendency toward the decreased risk of HDMTX toxicity was present in three SNPs: TYMS 2R>3R and mucositis (dominant, OR=0.66, 95% CI=0.47–0.94); RFC1 80A>G and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16–0.76); and MTHFR 1298A>C and renal toxicity (allelic, OR=0.41, 95% CI=0.18–0.97). Since the data of prognosis outcomes was substantially lacking, current studies were underpowered to investigate the genetic association.
Conclusions: We conclude that genotyping of MTHFR and/or ABCB1 polymorphisms prior to treatment, MTHFR 677C>T particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.

研究目的：高剂量甲氨蝶呤（High-dose methotrexate, HDMTX）是治疗多种血液系统恶性肿瘤的主流治疗药物，其药代动力学特征与毒性反应存在显著的个体间差异。目前已有大量研究探讨HDMTX相关的遗传关联，但研究结果存在分歧，这给其临床应用带来了复杂性。因此，本系统评价旨在明确HDMTX通路内基因变异的作用，填补基础研究与临床实践之间的认知鸿沟。

研究方法：检索自建库至2020年11月的EMBASE、PubMed、Cochrane对照试验中心注册库（Cochrane Central Register of Controlled Trials, CENTRAL）以及ClinicalTrials.gov数据库。本研究纳入HDMTX通路内的12个单核苷酸多态性（single-nucleotide polymorphisms, SNPs），涉及RFC1、SLCO1B1、ABCB1、FPGS、GGH、MTHFR、DHFR、TYMS及ATIC基因。采用Cochrane协作网Review Manager 5.3软件进行荟萃分析，通过比值比（odds ratios, ORs）或风险比（hazard ratios, HRs）及其95%置信区间（95% confidence interval, 95% CI）分析SNPs与临床结局的关联。本研究严格遵循PRISMA指南实施。

研究结果：共纳入34项研究，涉及4102名受试者用于关联分析。本研究对涉及MTHFR、RFC1、ABCB1、SLCO1B1、TYMS、FPGS及ATIC基因的9个SNPs进行了分析，目前尚无研究报道GGH与DHFR基因的多态性。有2个SNPs与HDMTX毒性风险升高存在统计学关联：MTHFR 677C>T与肝毒性（显性模型：OR=1.52，95%CI=1.03~2.23；隐性模型：OR=1.68，95%CI=1.10~2.55；等位基因模型：OR=1.41，95%CI=1.01~1.97）、黏膜炎（显性模型：OR=2.11，95%CI=1.31~3.41；等位基因模型：OR=1.91，95%CI=1.28~2.85）及肾毒性（隐性模型：OR=3.54，95%CI=1.81~6.90；等位基因模型：OR=1.89，95%CI=1.18~3.02）相关；ABCB1 3435C>T与肝毒性（显性模型：OR=3.80，95%CI=1.68~8.61）相关。另有3个SNPs表现出降低HDMTX毒性风险的趋势：TYMS 2R>3R与黏膜炎（显性模型：OR=0.66，95%CI=0.47~0.94）；RFC1 80A>G与肝毒性（隐性模型：OR=0.35，95%CI=0.16~0.76）；MTHFR 1298A>C与肾毒性（等位基因模型：OR=0.41，95%CI=0.18~0.97）。由于预后结局数据严重缺失，现有研究的统计效力不足以开展遗传关联分析。

研究结论：本研究认为，在治疗前对MTHFR和/或ABCB1基因多态性进行基因分型（尤其是MTHFR 677C>T），或可用于优化HDMTX治疗方案，从而降低血液系统恶性肿瘤患者的毒性反应发生风险。