Dataset Information

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer.

ABSTRACT: BACKGROUND:Breast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers. METHODS:We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR), and the ribonucleotide reductase M1 gene (RRM1) in 342 MBC patients treated with capecitabine-based chemotherapy. The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson's ?2 test, and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis. The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci (eQTL) browser online tools. RESULTS:We found 4 positive sites for HFS in the TYMS and MTHFR genes: TYMS rs2606241 (P?=?0.022), TYMS rs2853741 (P?=?0.019), MTHFR rs3737964 (P?=?0.029), and MTHFR rs4846048 (P?=?0.030). Logistic regression analyses showed that the genotype AG of MTHFR rs3737964 [odds ratio (OR)?=?0.54, 95% confidence interval (CI) 0.31-0.97, P?=?0.038] and MTHFR rs4846048 (OR?=?0.54, 95% CI 0.30-0.98, P?=?0.042) were protective factors of HFS, whereas the genotype CT of TYMS rs2853741 (OR?=?2.25, 95% CI 1.31-3.87, P?=?0.012) increased the risk of HFS. The association between the genotype GT of TYMS rs2606241 (OR?=?1.27, 95% CI 0.73-2.23, P?=?0.012) and HFS was uncertain. Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis. CONCLUSIONS:We have identified four potentially useful pharmacogenetic markers, TYMS rs2606241, TYMS rs2853741, MTHFR rs3737964, and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.

SUBMITTER: Lin S

PROVIDER: S-EPMC6787984 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer.

Lin Shaoyan S Yue Jian J Guan Xiuwen X Yuan Peng P Wang Jiayu J Luo Yang Y Fan Ying Y Cai Ruigang R Li Qiao Q Chen Shanshan S Zhang Pin P Li Qing Q Ma Fei F Xu Binghe B

Cancer communications (London, England) 20191011 1

<h4>Background</h4>Breast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic bi ...[more]

PMID: 31601265

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Project description:Importance:Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective:To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants:This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions:Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures:Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results:In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P?=?.38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P?=?.001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P?=?.001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P?=?.003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P?<?.001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P?=?.001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P?<?5?×?10-8), including a novel DPYD variant (rs75267292; P?=?1.57?×?10-10), and variants in the MACF1 (rs183324967, P?=?4.80?×?10-11; rs148221738, P?=?5.73?×?10-10) and SPRY2 (rs117876855, P?<?1.01?×?10-8; rs139544515, P?=?1.30?×?10-8) genes involved in wound healing. Conclusions and Relevance:Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration:clinicaltrials.gov Identifier: NCT00486213.

Dataset Information

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer.

Publications

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer.

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