Dataset Information

Variations within 3'-UTR of MDM4 gene contribute to clinical outcomes of advanced non-small cell lung cancer patients following platinum-based chemotherapy.

ABSTRACT: Single-nucleotide polymorphism (SNPs) in microRNA (miRNA)-binding sites may modulate the posttranscriptional regulation of gene expression and explain individual sensitivity to platinum agents. This study aimed to investigate the impact of SNPs located at 3'-untranslated region (UTR) of MDM4 gene, on clinical outcomes of advanced non-small cell lung cancer (NSCLC) patients. Four SNPs were genotyped by using DNA from blood samples of advanced NSCLC patients (642 in the Discovery set and 330 in the Replication set) and were analyzed the relationships with clinical outcomes. Carriers with rs10900598 CC genotype and rs4245739 AC genotype showed increased overall survival (OS) than those with AA genotype (P = 0.017 and P = 0.037, respectively) in the Discovery set and after pooling results from the Replication set. A combined effect on survival of variant alleles was also concluded and validated. Stratification analysis revealed that the effect of MDM4 SNPs was more pronounced in lung adenocarcinoma (LAC) subgroups. A reduced expression of the reporter gene for the C allele of rs4245739 was observed in NSCLC cells using luciferase reporter gene assays. Taken together, our results demonstrate that genetic variations in 3'-UTR of MDM4 gene may influence outcomes of advanced NSCLC by miRNAs-mediated regulation.

SUBMITTER: Yang Y

PROVIDER: S-EPMC5369965 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Variations within 3'-UTR of MDM4 gene contribute to clinical outcomes of advanced non-small cell lung cancer patients following platinum-based chemotherapy.

Yang Yang Y Gao Wen W Ding Xi X Xu Wen W Liu Di D Su Bo B Sun Yifeng Y

Oncotarget 20170301 10

Single-nucleotide polymorphism (SNPs) in microRNA (miRNA)-binding sites may modulate the posttranscriptional regulation of gene expression and explain individual sensitivity to platinum agents. This study aimed to investigate the impact of SNPs located at 3'-untranslated region (UTR) of MDM4 gene, on clinical outcomes of advanced non-small cell lung cancer (NSCLC) patients. Four SNPs were genotyped by using DNA from blood samples of advanced NSCLC patients (642 in the Discovery set and 330 in th ...[more]

PMID: 27462918

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Project description:ObjectivesFood and Drug Administration (FDA) approved crizotinib for advanced ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) patients due to a single-arm study PROFILE 1001. However, there is no direct comparison between crizotinib and platinum-pemetrexed chemotherapy.Materials and methodsClinical data of advanced ROS1+NSCLC patients treated with first-line crizotinib or platinum-pemetrexed chemotherapy between August 2010 and December 2017 were analyzed.ResultsSeventy-seven patients were eligible, including 30 (39.0%) in the crizotinib group and 47 (61.0%) in the platinum-pemetrexed chemotherapy group. The median follow-up was 28.1 months (95% confidence interval [CI]: 19.2-39.0). The objective response rate (ORR) of crizotinib (86.7%, 95% CI: 73.3-96.7) was higher than that of platinum-pemetrexed chemotherapy (44.7%, 95% CI: 29.8-57.4, P < .001). The disease control rate (DCR) was 96.7% (95% CI: 90.0-100) in the crizotinib group and 85.1% (95% CI: 74.5-95.7) in the chemotherapy group (P = .140). Significantly longer progression-free survival (PFS) was observed in the patients treated with crizotinib (18.4 months, 95% CI: 6.4-30.3) versus platinum-pemetrexed chemotherapy (8.6 months, 95% CI: 6.9-10.3, P < .001). Overall survival (OS) was also compared between the two groups and no significant difference was seen (Not reach vs 28.4 months [95% CI: 20.7-36.0], P = .176). Notably, a total of 37 patients have treatment crossover after the failure of first-line treatment. Among those patients, difference in OS was not statistically significant between seven patients who have given first-line crizotinib (38.6 months, 95% CI: 0-81.0) and 30 patients who have given platinum-pemetrexed chemotherapy initially (32.8 months, 95% CI: 11.9-53.8, P = .805).ConclusionsOur results suggested that first-line crizotinib had higher ORR and longer PFS than platinum-pemetrexed chemotherapy in patients with advanced ROS1+NSCLC, but the differences were not observed for OS.

Project description:Background Platinum-based chemotherapy (PC) and immunotherapy plus platinum-based chemotherapy (IPC) remain the first-line treatment for advanced NSCLC. But only a minority patients benefit from PC, and existing biomarkers, such as PD-L1, have been shown to be defective in predicting the efficacy of IPC. Highlighting the need to identify novel biomarkers for the efficacy of PC and IPC. DNA damage repair (DDR) mutations are known to predict response to PC in solid tumors. However, the predictive value of DDR in PC and IPC of NSCLC remains unclear. Methods Patients diagnosed with advanced or metastatic NSCLC were retrospectively included if they underwent next generation sequencing prior to starting treatment. Primary endpoints were to explore whether DDR mutations (DDRmut) are associated with clinical outcomes of PC and IPC. Secondary end point were to explore the association between DDRmut and the choice to add immunotherapy to chemotherapy, and the impact of different DDR pathways on efficacy in PC and IPC. Results DDRmut showed a strong association with tumor mutation burden-high (TMB-H) versus DDR wild-type (DDRwt) and higher rates of PD-L1 TPS ≥50% positivity. In 63 patients treated with PC, ORRs were 15.38% and 2.86% for DDRmut and DDRwt subgroup (P=0.1536), and DCRs were 88.46% and 45.72% (P=0.00097) at 6 months after PC. The DDRmut patients had significantly improved median PFS (mPFS) and median overall survival (mOS) than DDRwt group (mPFS: 7.6 vs. 3.9 months, HR =1.93, 95% CI: 1.09 to 3.14, P=0.0220. mOS: 29.9 vs. 20.7 months, HR =2.31, 95% CI: 1.09 to 4.9, P=0.0250). Moreover, among 37 patients treated with IPC, ORRs were 45% and 11.76% for DDRmut and DDRwt patients (P=0.0365), and the DCRs were 95% and 70.58% (P=0.0752), respectively at 6 months after IPC. The DDRmut patients had significantly improved mPFS compared to the DDRwt group (19.5 vs. 4.5 months, HR =3.28, 95% CI: 1.53 to 9.56, P=0.0022). In DDRmut group, mPFS of IPC recipients was significantly better than that of PC recipients (19.5 vs. 7.6 months, HR =2.09, 95% CI: 0.98 to 4.42, P=0.050). Conclusions There is potential for DDR to serve as a positive predictor of PC and IPC in advanced NSCLC patients.

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Variations within 3'-UTR of MDM4 gene contribute to clinical outcomes of advanced non-small cell lung cancer patients following platinum-based chemotherapy.

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Variations within 3'-UTR of MDM4 gene contribute to clinical outcomes of advanced non-small cell lung cancer patients following platinum-based chemotherapy.

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