title: 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.
authors.affiliation: Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea.|Cell and Matrix Research Institute, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Hong
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.|Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Shin Yup
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea.|Cell and Matrix Research Institute, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Jin Eun
authors.initials: JE
authors.lastname: Choi
authors.affiliation: Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Jin
authors.affiliation: Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Baek
authors.affiliation: Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Radiology, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Shin
authors.affiliation: Department of Pathology, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Biostatistics Center, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Won Kee
authors.initials: WK
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.|Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Seung Soo
authors.initials: SS
authors.lastname: Yoo
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Jaehee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Seung Ick
authors.initials: SI
authors.lastname: Cha
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Konyang University Hospital, Daejeon, Republic of Korea.
authors.forename: Ji Woong
authors.initials: JW
authors.lastname: Son
authors.affiliation: Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea.|Cell and Matrix Research Institute, Kyungpook National University Medical Center, Daegu, Republic of Korea.|Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.|Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002945:Cisplatin / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D017239:Paclitaxel / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C494069:ETS2 protein, human; C551557:MIRN149 microRNA, human; D035683:MicroRNAs; D050787:Proto-Oncogene Protein c-ets-2; D017239:Paclitaxel; D002945:Cisplatin
keywords: chemotherapy; miRNA target sites; non-small cell lung cancer; polymorphisms; response