Genetic polymorphism of SLC31A1 is associated with clinical outcomes of platinum-based chemotherapy in non-small-cell lung cancer patients through modulating microRNA-mediated regulation
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Chang Sun1,*, Zhuojun Zhang1,*, Jingbo Qie1, Yi Wang1, Ji Qian1, Jiucun Wang1, Junjie Wu1,2, Qiang Li2, Chunxue Bai3, Baohui Han4, Zhiqiang Gao4, Jibin Xu5, Daru Lu1, Li Jin1 and Haijian Wang1
1State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
2Department of Respiratory and Critical Care Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China
3Department of Pulmonary Medicine, Zhongshan Hospital of Fudan University, Shanghai, China
4Department of Pneumology, Chest Hospital, Shanghai Jiaotong University, Shanghai, China
5Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China
*These authors contributed equally to this work
Haijian Wang, email: [email protected]
Keywords: NSCLC; pharmacogenetics; SLC31A1; SNP; microRNA
Received: December 21, 2017 Accepted: February 27, 2018 Published: May 08, 2018
SLC31A1 is the major transporter for platinum drug intake, its expression correlates with drug disposition and response. In 1004 Chinese NSCLC patients with platinum-based chemotherapy, we investigated the association between SLC31A1 polymorphisms and clinical outcomes. Heterozygotes of rs10759637 at 3ʹUTR was associated with severe thrombocytopenia (odds ratio [OR]: 2.69; P = 0.012) and shorter overall survival (hazard ratio [HR]: 1.24; P = 0.005). Variant homozygote of rs2233914 was correlated with longer overall survival (hazard ratio [HR]: 0.73; P = 0.008). Haplotype and diplotype of these linked SNPs were associated with hematologic toxicities. In stratification analyses, rs10759637 and rs2233914 consistently correlated with overall survival in specific subgroups such as men, smoker, patients older than 58 years, or with ECOG PS 0-1, or with squamous cell carcinoma. rs10759637 could change the local structure of 3ʹUTR harboring putative binding sites for hsa-miR-29, whose transfection into 16HBE cells resulted in remarkable suppression of gene expression. The rs10759637 variant significantly correlated with lowered luciferase activity in reporter assays and decreased expression of SLC31A1 transcript in tumorous tissues. The study thereby identified functional polymorphism of SLC31A1 that modulates miRNA-3ʹUTR interaction and gene expression as potential pharmacogenetic biomarker for clinical outcomes of platinum-based chemotherapy in NSCLC patients.
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