Oncotarget

Research Papers:

Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose

Dandan Yin, Xuyang Xia, Junlong Zhang, Shouyue Zhang, Fei Liao, Ge Zhang, Yan Zhang, Qianqian Hou, Xue Yang, Hong Wang, Zhigui Ma, Heyao Wang, Yiping Zhu, Wei Zhang, Yuelan Wang, Bo Liu, Lanlan Wang, Heng Xu and Yang Shu _

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Oncotarget. 2017; 8:13575-13585. https://doi.org/10.18632/oncotarget.14594

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Abstract

Dandan Yin1,*, Xuyang Xia1,*, Junlong Zhang2,*, Shouyue Zhang1,*, Fei Liao1, Ge Zhang3, Yan Zhang4, Qianqian Hou1, Xue Yang5, Hong Wang5, Zhigui Ma3, Heyao Wang6, Yiping Zhu3, Wei Zhang7, Yuelan Wang1, Bo Liu1, Lanlan Wang2, Heng Xu1,2, Yang Shu1

1Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China

2Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

3Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China

4Department of Thoracic Oncology, Cancer Center, National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

5Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA

6Department of Precision Medicine, China-Japan Friendship Hospital, Beijing, China

7Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China

*These authors contributed equally to this work

Correspondence to:

Lanlan Wang, email: [email protected]

Heng Xu, email: [email protected]

Yang Shu, email: [email protected]

Keywords: meta-analysis, NUDT15, thiopurines-induced myelotoxicity, intolerance dose

Received: November 08, 2016     Accepted: January 04, 2017     Published: January 11, 2017

ABSTRACT

Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13–10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an α helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians.


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