Genetic polymorphism ofSLC31A1is associated with clinical outcomes of platinum-based chemotherapy in non-small-cell lung cancer patients through modulating microRNA-mediated regulation

Abstract

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 3′UTR 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 3′UTR 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-3′UTR interaction and gene expression as potential pharmacogenetic biomarker for clinical outcomes of platinum-based chemotherapy in NSCLC patients.

A pharmacogenetics study of platinum-based chemotherapy in lung cancer: ABCG2 polymorphism and its genetic interaction with SLC31A1 are associated with response and survival

“…The main characteristics for the 1004 eligible patients of the two panel cohorts in total and their clinical outcomes including objective response, toxicity and survival are summarized in Table 1 were documented in detail in our recent report 9 . Briefly, 177 (18.1%) of the 975 patients evaluated were responders (one was complete response, CR, and 176 were partial response, PR), and 798 (81.9%) were non-responders (610 showed stable disease, SD, and 188 showed progressive disease, PD).…”

“…We have recently reported that SLC31A1 polymorphisms overall were not associated with response 9 , except rs2233914 (G/A), a common variant at 5' flanking region upstream the transcription start site that was associated with poor response in dominant model (OR 0.67; 95% CI 0.48-0.95; P = 0.024) ( Supplemental Table 4 ). In an effort to interrogate pharmacogenetically relevant genetic interaction between platinum drug intake and export pathways, we investigated the joint effect of ABCG2 (rs1871744 and rs2231142) and SLC31A1 (rs2233914) genotypes on response in the total cohort (Table 4 ).…”

“…All of the 1004 patients are Chinese Han and were histologically diagnosed with stage Ⅲ-Ⅳ NSCLC between March 2005 and January 2010 from five hospitals in the East of China: Shanghai Chest Hospital, Shanghai Zhongshan Hospital, Shanghai Changhai Hospital, Shanghai Changzheng Hospital, and Cancer Hospital of Jiangsu Province. The recruitment criteria, the demographic and baseline characteristics including gender, age at diagnosis, smoking status, ECOG performance status, TNM stage, and histological type, were described in detail in our previous reports 9 , 14 - 17 . The chemotherapeutic regimens were as follows: either cisplatin (75 mg/m 2 ) or carboplatin (at an area under the curve 5), both administered on day 1 every 3 weeks, in combination with navelbine (25 mg/m 2 ) on days 1 and 8 every 3 weeks, or gemcitabine (1250 mg/m 2 ) on days 1 and 8 every 3 weeks, or paclitaxel (175 mg/m 2 ) on day 1 every 3 weeks, or docetaxel (75 mg/m 2 ) on day 1 every 3 weeks.…”

“…The aberrant expression and dysfunction of platinum transporters, which are largely ascribed to the functional polymorphisms of their coding genes, may influence interindividual variability in drug tissue concentration and therapeutic effects. We have recently reported that a functional SNP, rs10759637, at the 3′ untranslated region (3′UTR) of SLC31A1 gene could affect the microRNA-3′UTR interaction, modulate gene expression, and thereby is associated with toxicity and survival of NSCLC patients receiving platinum-based chemotherapy 9 . Although the association of ABCG2 polymorphism with drug resistance has been addressed in a range of solid tumors including lung cancer 5 , 10 - 13 , its relevance in outcome prediction for platinum-based chemotherapy of NSCLC is still elusive, and particularly, pharmacogenetic interaction between platinum uptake and efflux transporter genes is largely unknown.…”

MAPK-induced miR-29 targets MAFG and suppresses melanoma development

“…Since we did not observe changes in the expression of the validated miR-29 targets AKT3, MCL1, and DNMT3B, we identified new targets that might constitute vulnerabilities of melanoma. Of the 9 genes identified by our approach (KCTD5, MYBL2, SLC31A1, MAFG, RCC2, TUBB2A, SH3BP5L, SMS and NCKAP5L), RCC2, MYBL2 and SLC31A1 have previously been identified as miR-29 targets (Martinez et al 2011;Matsuo et al 2013;Wu et al 2013;Hu et al 2014;Sun et al 2018). We selected MAFG for further analyses because the protein is stabilized by ERK-mediated phosphorylation (Fang et al 2016), suggesting that MAPK signaling converges on MAFG via ERK and miR-29.…”