Dataset Information

A genetic variation in microRNA target site of ETS2 is associated with clinical outcomes of paclitaxel-cisplatin chemotherapy in non-small cell lung cancer.

ABSTRACT: The present study was performed to investigate the association of single nucleotide polymorphisms (SNPs) located in the miRNA target sites with the clinical outcomes of first line paclitaxel-cisplatin chemotherapy in advanced NSCLC. Eighty SNPs in miRNA binding sites of cancer related genes selected from 18,500 miRNA:target bindings in crosslinking, ligation, and sequencing of hybrids (CLASH) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry-based genotype assay. qRT-PCR and luciferase assay were conducted to examine functional relevance of potentially functional SNPs in miRNA binding sites. Of the 80 SNPs analyzed, 16 SNPs were significantly associated with the clinical outcomes after chemotherapy. Among these, ANAPC1 rs3814026C>T, ETS2 rs461155A>G, SORBS1 rs7081076C>A and POLR2A rs2071504C>T could predict both chemotherapy response and survival. Notably, ETS2 rs461155A>G was significantly associated with decreased ETS2 mRNA expression in both tumor and paired normal lung tissues (Ptrend = 4 × 10-7, and 3 × 10-4, respectively). Consistently, a decreased expression of the reporter gene for the G allele of rs461155 compared with the A allele was observed by luciferase assay. These findings suggest that the four SNPs, especially ETS2 rs461155A>G, could be used as biomarkers predicting the clinical outcomes of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.

SUBMITTER: Hong MJ

PROVIDER: S-EPMC4941289 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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A genetic variation in microRNA target site of ETS2 is associated with clinical outcomes of paclitaxel-cisplatin chemotherapy in non-small cell lung cancer.

Hong Mi Jeong MJ Lee Shin Yup SY Choi Jin Eun JE Jin Cheng Cheng CC Kang Hyo Jung HJ Baek Sun Ah SA Lee So Yeon SY Shin Kyung Min KM Jeong Ji Yun JY Lee Won Kee WK Yoo Seung Soo SS Lee Jaehee J Cha Seung Ick SI Kim Chang Ho CH Son Ji Woong JW Park Jae Yong JY

Oncotarget 20160301 13

The present study was performed to investigate the association of single nucleotide polymorphisms (SNPs) located in the miRNA target sites with the clinical outcomes of first line paclitaxel-cisplatin chemotherapy in advanced NSCLC. Eighty SNPs in miRNA binding sites of cancer related genes selected from 18,500 miRNA:target bindings in crosslinking, ligation, and sequencing of hybrids (CLASH) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry-based genotype ...[more]

PMID: 26893365

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Project description:The use of weekly chemotherapy for the treatment of patients with advanced-stage serous-type epithelial Tubo-ovarian cancer (ETOC), and primary peritoneal serous carcinoma (PPSC) is acceptable as the front-line postoperative chemotherapy after primary cytoreductive surgery (PCS). The main component of dose-dense chemotherapy is weekly paclitaxel (80 mg/m2), but it would be interesting to know what is the difference between combination of triweekly cisplatin (20 mg/m2) or triweekly carboplatin (carboplatin area under the curve 5-7 mg/mL per min [AUC 5-7]) in the dose-dense paclitaxel regimen. Therefore, we compared the outcomes of women with Gynecology and Obstetrics (FIGO) stage IIIC ETOC and PPSC treated with PCS and a subsequent combination of dose-dense weekly paclitaxel and triweekly cisplatin (paclitaxel-cisplatin) or triweekly carboplatin using AUC 5 (paclitaxel-carboplatin). Between January 2010 and December 2016, 40 women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC EOC, FTC, or PPSC were enrolled, including 18 treated with paclitaxel-cisplatin and the remaining 22 treated with paclitaxel-carboplatin. There were no statistically significant differences in disease characteristics of patients between two groups. Outcomes in paclitaxel-cisplatin group seemed to be little better than those in paclitaxel-carboplatin (median progression-free survival [PFS] 30 versus 25 months as well as median overall survival [OS] 58.5 versus 55.0 months); however, neither reached a statistically significant difference. In terms of adverse events (AEs), patients in paclitaxel-carboplatin group had more AEs, with a higher risk of neutropenia and grade 3/4 neutropenia, and the need for a longer period to complete the front-line chemotherapy, and the latter was associated with worse outcome for patients. We found that a period between the first-time chemotherapy to the last dose (6 cycles) of chemotherapy >21 weeks was associated with a worse prognosis in patients compared to that ?21 weeks, with hazard ratio (HR) of 81.24 for PFS and 9.57 for OS. As predicted, suboptimal debulking surgery (>1 cm) also contributed to a worse outcome than optimal debulking surgery (?1 cm) with HR of 14.38 for PFS and 11.83 for OS. Based on the aforementioned findings, both regimens were feasible and effective, but maximal efforts should be made to achieve optimal debulking surgery and following the on-schedule administration of dose-dense weekly paclitaxel plus triweekly platinum compounds. Randomized trials validating the findings are warranted.

Project description:BackgroundOvarian malignancies are often diagnosed in advanced stage and at the same time resistance to treatment, both intrinsic and developed during treatment, is sometimes observed. These facts underscore the need for new markers of ovarian cancer risk, as well as markers of treatment effectiveness.MethodsIn this study we genotyped 225 ovarian cancer patients, 64 breast and ovarian cancer patients and 348 healthy controls. In total, 12 polymorphic variants and 2 deletions in PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes were analyzed using ASA-PCR, RFLP-PCR, multiplex-PCR and sequencing.ResultsTen genetic polymorphisms were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. Impact of PGR gene polymorphisms on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers (in presence of p.Val660Leu variant- OR 2,82; p = 0,010), which confirms the difference in modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in all groups excluding the group with BRCA1 mutation. Cumulative risk analysis revealed 3 unfavorable variants that increased significantly the risk of developing ovarian cancer (p.Ile1145 = ABCB1+ p.Asp1853Asn ATM+ p.Ser406Ala ATP7B- OR 7,47; p = 0,002) and significantly modified the progression free survival (PFS) of the patients, and also two favorable genotypes which protected against ovarian cancer (p.Arg952Lys ATP7B+ p.Arg72Pro TP53- OR 0,50; p = 0,008). PFS analysis for carriers of favorable versus unfavorable genotypes emphasized the impact of the regulation of cell cycle (p.Asp1853Asn ATM) and active transport of xenobiotics (p.Ser894Ala/Thr ABCB1) on the risk of disease progression (HR 3,81; p = 0,010) after paclitaxel/cisplatin chemotherapy.ConclusionsThe unfavorable genetic variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors.

Dataset Information

A genetic variation in microRNA target site of ETS2 is associated with clinical outcomes of paclitaxel-cisplatin chemotherapy in non-small cell lung cancer.

Publications

A genetic variation in microRNA target site of ETS2 is associated with clinical outcomes of paclitaxel-cisplatin chemotherapy in non-small cell lung cancer.

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