Yangki Seok1,2, Hyo-Gyoung Kang3,4, Shin Yup Lee1,5, Ji Yun Jeong6, Jin Eun Choi3,4, Deuk Kju Jung3,7, Cheng Cheng Jin3,7, Mi Jeong Hong3,7, Sook Kyung Do3,7, Won Kee Lee8, Ji Young Park6, Kyung Min Shin9, Seung Soo Yoo1,5, Jaehee Lee5, Sukki Cho10, Seung Ick Cha5, Chang Ho Kim5, Sanghoon Jheon10, Eung Bae Lee11,12, Jae Yong Park13,14,15,16,17. 1. Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea. 2. Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 3. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 4. Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 5. Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 6. Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 7. BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea. 8. Biostatistics Medical Research Collaboration Center, Kyungpook National University Hospital and Kyungpook National University School of Medicine, Daegu, Republic of Korea. 9. Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 10. Department of Thoracic and Cardiovascular Surgery, Seoul National University School of Medicine, Seoul, Republic of Korea. 11. Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea. bay@knu.ac.kr. 12. Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. bay@knu.ac.kr. 13. Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea. jaeyong@knu.ac.kr. 14. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. jaeyong@knu.ac.kr. 15. Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. jaeyong@knu.ac.kr. 16. Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. jaeyong@knu.ac.kr. 17. BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea. jaeyong@knu.ac.kr.
Abstract
BACKGROUND: This study was conducted to determine whether single-nucleotide polymorphisms (SNPs) in EMT-related genes may influence the prognosis of NSCLC after surgery. METHODS: There were 88 SNPs in EMT-related genes evaluated in a discovery set of 376 patients who underwent curative surgery for NSCLC. Significantly, 14 SNPs were evaluated in a validation set of 428 patients. Luciferase assay and RT-PCR were conducted to examine functional relevance of polymorphisms. RESULTS: Fourteen SNPs that were associated with survival outcomes in a discovery set were selected for validation. Among those, two SNPs (FOXF2 rs1711972A>C and HEYL rs784621G>A) were replicated in a validation study. In combined analysis, FOXF2 rs1711972 AC+CC genotype was associated with significantly better overall survival (OS) and disease-free survival (DFS) compared with AA genotype (adjusted hazard ratio [aHR] for OS = 0.67, 95% confidence interval [CI] 0.51-0.88, P = 0.004; and aHR for DFS = 0.77, 95% CI 0.62-0.95, P = 0.01). HEYL rs784621 AA genotype exhibited a significantly worse OS compared with GG+GA genotype (aHR for OS = 2.65, 95% CI 1.63-4.31, P = 8 × 10-5). FOXF2 rs1711972C allele had a significantly increased promoter activity than rs1711972A allele (P = 0.01), and HEYL rs784621A allele had a significantly lower promoter activity than rs784621G allele (P = 0.004). FOXF2 rs1711972A>C was significantly associated with increased FOXF2 mRNA expression. CONCLUSIONS: FOXF2 rs1711972A>C and HEYL rs784621G>A were associated with survival outcomes of surgically treated NSCLC. These SNPs may help to identify patients at high risk of poor disease outcomes.
BACKGROUND: This study was conducted to determine whether single-nucleotide polymorphisms (SNPs) in EMT-related genes may influence the prognosis of NSCLC after surgery. METHODS: There were 88 SNPs in EMT-related genes evaluated in a discovery set of 376 patients who underwent curative surgery for NSCLC. Significantly, 14 SNPs were evaluated in a validation set of 428 patients. Luciferase assay and RT-PCR were conducted to examine functional relevance of polymorphisms. RESULTS: Fourteen SNPs that were associated with survival outcomes in a discovery set were selected for validation. Among those, two SNPs (FOXF2 rs1711972A>C and HEYL rs784621G>A) were replicated in a validation study. In combined analysis, FOXF2rs1711972 AC+CC genotype was associated with significantly better overall survival (OS) and disease-free survival (DFS) compared with AA genotype (adjusted hazard ratio [aHR] for OS = 0.67, 95% confidence interval [CI] 0.51-0.88, P = 0.004; and aHR for DFS = 0.77, 95% CI 0.62-0.95, P = 0.01). HEYLrs784621 AA genotype exhibited a significantly worse OS compared with GG+GA genotype (aHR for OS = 2.65, 95% CI 1.63-4.31, P = 8 × 10-5). FOXF2 rs1711972C allele had a significantly increased promoter activity than rs1711972A allele (P = 0.01), and HEYL rs784621A allele had a significantly lower promoter activity than rs784621G allele (P = 0.004). FOXF2 rs1711972A>C was significantly associated with increased FOXF2 mRNA expression. CONCLUSIONS:FOXF2 rs1711972A>C and HEYL rs784621G>A were associated with survival outcomes of surgically treated NSCLC. These SNPs may help to identify patients at high risk of poor disease outcomes.