Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity

详细信息    查看全文

• 作者：Didier Meulendijks ; Linda M. Henricks ; Ursula Amstutz ; Tanja K. Froehlich ; Carlo R. Largiadè ; r ; Jos H. Beijnen ; Anthonius de Boer ; Maarten J. Deenen ; Annemieke Cats and Jan H.M. Schellens
• 关键词：dihydropyrimidine dehydrogenase ; miR-27a ; microRNA ; capecitabine ; 5-fluorouracil ; toxicity
• 刊名：International Journal of Cancer
• 出版年：2016
• 出版时间：June 01 2016
• 年：2016
• 卷：138
• 期：11
• 页码：2752-2761
• 全文大小：511K
• ISSN：1097-0215

文摘

The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129-5923C>G and c.1601G>A. The predictive value of MIR27A variants for early-onset grade ≥3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild-type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for ≥1 variant MIR27A allele vs. none, 95% CI: 0.87–1.82, p = 0.228). In contrast, in patients carrying DPYD variants, the presence of ≥1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95% CI: 1.24–19.7, p = 0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, 95% CI: 0.47−18.0, p = 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27–4.37, p = 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.06−1.17, p = 0.081). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83–15.7, p = 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity.