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

// Mi Jeong Hong 1, 2, * , Shin Yup Lee 3, 4 , Jin Eun Choi 1, 2 , Cheng Cheng Jin 1 , Hyo Jung Kang 1 , Sun Ah Baek 1 , So Yeon Lee 4 , Kyung Min Shin 5 , Ji Yun Jeong 6 , Won Kee Lee 7 , Seung Soo Yoo 3, 4 , Jaehee Lee 3 , Seung Ick Cha 3 , Chang Ho Kim 3 , Ji Woong Son 8 , Jae Yong Park 1, 2, 3, 4, * 1 Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea 2 Cell and Matrix Research Institute, Kyungpook National University Medical Center, Daegu, Republic of Korea 3 Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea 4 Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea 5 Department of Radiology, Kyungpook National University Medical Center, Daegu, Republic of Korea 6 Department of Pathology, Kyungpook National University Medical Center, Daegu, Republic of Korea 7 Biostatistics Center, School of Medicine, Kyungpook National University, Daegu, Republic of Korea 8 Department of Internal Medicine, Konyang University Hospital, Daejeon, Republic of Korea * These authors have contributed equally to this work Correspondence to: Shin Yup Lee, e-mail: shinyup@knu.ac.kr Keywords: non-small cell lung cancer, miRNA target sites, polymorphisms, chemotherapy, response Received: October 02, 2015      Accepted: February 06, 2016      Published: February 17, 2016 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.