Oosterom Natanja, Berrevoets Marijn, den Hoed Marissa A H, Zolk Oliver, Hoerning Susanne, Pluijm Saskia M F, Pieters Rob, de Jonge Robert, Tissing Wim J E, van den Heuvel-Eibrink Marry M, Heil Sandra G
Princess Máxima Center for Pediatric Oncology, Utrecht.
Department of Clinical Chemistry, Erasmus University Medical Center.
Pharmacogenet Genomics. 2018 Oct;28(10):223-229. doi: 10.1097/FPC.0000000000000352.
Methotrexate (MTX) is an important drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). MTX is cytotoxic as it impairs DNA and RNA synthesis by inhibiting the enzymes dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS). The association between genetic variants within the TYMS gene and MTX-induced toxicity has been studied, but results are inconsistent. We determined the role of three previously described variants within the TYMS gene and MTX-induced oral mucositis in a prospective cohort of Dutch children with ALL and performed a meta-analysis of the previous results.
We analyzed the presence of a 28-base pair tandem repeat (rs34743033; 2R3R), a single nucleotide polymorphism present within the 28-base pair repeat on the 3R allele (rs2853542; 3RG>C) and a 6-base pair deletion (rs15126436; TTAAAG) within the TYMS gene in germline DNA of 117 pediatric patients with ALL. Oral mucositis was defined as grade≥3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.3.0. Data were analyzed for the individual rs34743033 (2R3R) and rs151264360 (6 bp deletion) polymorphisms, whereas rs2853542 (3RG>C) was combined with rs34743033 (2R3R) and analyzed according to predicted expression levels of TYMS: low expression (2R/2R, 2R/3RC and 3RC/3RC), median expression (2R/3RG and 3RC/3RG) and high expression (3RG/3RG). We performed a meta-analysis of the current literature on these polymorphisms in relation to oral mucositis using a fixed effects model.
The 2R2R genotype (rs34743033) was not significantly associated with developing MTX-induced oral mucositis compared with the 2R3R/3R3R genotypes, which was confirmed in a meta-analysis [odds ratio (OR): 1.17 (0.62-2.19)]. Patients carrying the low-expression TYMS genotype (2R2R, 2R3RC, 3RC3RC) had an increased odds of developing MTX-induced oral mucositis [OR: 2.42 (0.86-6.80)], which did not reach statistical significance. The 6-bp deletion [rs151264360, OR: 0.79 (0.20-3.19)] was not associated with the development of MTX-induced oral mucositis.
The TYMS 6-bp deletion and 2R3R polymorphism were not associated with MTX-induced oral mucositis. Validation studies in prospective cohorts are necessary to assess the possible role of the low-expression TYMS genotypes in relation to MTX-induced oral mucositis.
甲氨蝶呤（MTX）是治疗小儿急性淋巴细胞白血病（ALL）的一种重要药物。MTX具有细胞毒性，因为它通过抑制二氢叶酸还原酶（DHFR）和胸苷酸合成酶（TYMS）来损害DNA和RNA的合成。已对TYMS基因内的基因变异与MTX诱导的毒性之间的关联进行了研究，但结果并不一致。我们在一个荷兰ALL患儿的前瞻性队列中确定了TYMS基因中先前描述的三种变异与MTX诱导的口腔黏膜炎之间的作用，并对先前的结果进行了荟萃分析。
我们分析了117例ALL患儿生殖系DNA中TYMS基因内的一个28个碱基对的串联重复序列（rs34743033；2R3R）、3R等位基因上28个碱基对重复序列内的一个单核苷酸多态性（rs2853542；3RG>C）以及一个6个碱基对的缺失（rs15126436；TTAAAG）。根据美国国立癌症研究所不良事件通用术语标准（CTCAE）v.3.0，将口腔黏膜炎定义为≥3级。对个体rs34743033（2R3R）和rs151264360（6 bp缺失）多态性进行数据分析，而rs2853542（3RG>C）与rs34743033（2R3R）合并，并根据TYMS的预测表达水平进行分析：低表达（2R/2R、2R/3RC和3RC/3RC）、中等表达（2R/3RG和3RC/3RG）和高表达（3RG/3RG）。我们使用固定效应模型对当前关于这些多态性与口腔黏膜炎关系的文献进行了荟萃分析。
与2R3R/3R3R基因型相比，2R2R基因型（rs34743033）与发生MTX诱导的口腔黏膜炎无显著相关性，这在荟萃分析中得到了证实[比值比（OR）：1.17（0.62 - 2.19）]。携带低表达TYMS基因型（2R2R、2R3RC、3RC3RC）的患者发生MTX诱导的口腔黏膜炎的几率增加[OR：2.42（0.86 - 6.80）]，但未达到统计学显著性。6 bp缺失[rs151264360，OR：0.79（0.20 - 3.19）]与MTX诱导的口腔黏膜炎的发生无关。
TYMS基因的6 bp缺失和2R3R多态性与MTX诱导的口腔黏膜炎无关。有必要在前瞻性队列中进行验证研究，以评估低表达TYMS基因型与MTX诱导的口腔黏膜炎之间可能的关系。
