Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis
Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis
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DOI：
10.1016/j.phrs.2019.104594
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发表时间：
2020-02-01
影响因子：
9.3
通讯作者：
Largiader, Carlo R.
中科院分区：
文献类型：
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作者：
Hamzic, Seid;Kummer, Dominic;Largiader, Carlo R.
为了评估烯醇化酶超家族成员1基因（ENOSF1）中的c.742-227G > A （rs2612091）多态性和相邻的胸苷酸合成酶基因（TYMS）中的两个变体：5'VNTR 28bp重复序列（rs45445694）和3'UTR 6bp-indel （rs11280056）与氟嘧啶治疗的癌症患者的严重毒性之间的关联，我们进行了个体患者数据荟萃分析。只有调查上述所有三种具有氟嘧啶相关毒性的变异的研究才被纳入荟萃分析。使用多变量回归对每个研究分别进行关联检验。采用随机效应模型进行meta分析。采用单阶段多变量回归（包括独立SNP效应的检验）来研究变异的个体效应。对合并数据集进行多变量单倍型回归分析，以检验多snp效应。在包括2067例患者的4项研究中，1912例符合meta分析。所有变异均与严重手足综合征（HFS）完全相关（每等位基因TYMS 2R: OR = 1.50, p = 0.0002; TYMS 6bp-ins: OR = 1.42 p = 0.0036; ENOSF1 c.742-227G: OR = 1.64 p < 0.0001）。我们观察到forEIVOSPrc的独立效应。742- 227g5a和TYMS-28bV重复：每个毒性相关等位基因增加严重HFS的风险（OR = 1.32每个等位基因，p < 0.0001）。两种变体纯合子的患者发生严重HFS的风险是野生型患者的3倍。我们的研究结果证实了ENOSF1 c.742-227G和TYMS 2r等位基因在氟嘧啶相关HFS的发展中起重要作用。这表明这些基因在严重HFS的发展中具有重要功能。此外，这些变异可能有助于在调查HFS预防措施的研究中对患者进行分层。
To assess the proposed associations of the c.742-227G > A (rs2612091) polymorphism within the Enolase Superfamily Member 1 gene (ENOSF1) and two variants in the adjacent Thymidylate Synthase gene (TYMS): the 5'VNTR 28bp-repeat (rs45445694) and 3'UTR 6bp-indel (rs11280056) with severe toxicity in fluoropyrimidinetreated cancer patients, we performed an individual patient data meta-analysis. Only studies investigating all three-abovementioned variants with fluoropyrimidine-related toxicities were considered for meta-analysis. Associations were tested individually for each study using multivariate regression. Meta-analysis was performed using a random-effects model. One-stage multivariate regressions including tests for independent SNP effects were applied to investigate individual effects of the variants. Multivariate haplotype regression analyses were performed on a pooled dataset to test multi-SNP effects. Of four studies including 2'067 patients, 1'912 were eligible for meta-analysis. All variants were exclusively associated with severe hand-foot-syndrome (HFS) (TYMS 2R: OR = 1.50, p = 0.0002; TYMS 6bp-ins: OR = 1.42 p = 0.0036; ENOSF1 c.742-227G: OR = 1.64 p < 0.0001, per allele). We observed inependent effects forEIVOSPrc.742-227G 5 A and did TYMS-28bV repeat: each toxicity-associated allele increased the risk for severe HFS (OR = 1.32 per allele, p < 0.0001). Patients homozygous for both variants were at the 3-fold higher risk for severe HFS compared to wild-type patients. Our results confirm an essential role for ENOSF1 c.742-227G and TYMS 2R-alleles in the development of fluoropyrimidine-related HFS. This suggests an important function of these genes in the development of severe HFS. Furthermore, these variants might help stratify patients in studies investigating measures of HFS prevention.