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Fatty Acid Synthesis Pathway Genetic Variants and Clinical Outcome of Non-Small Cell Lung Cancer Patients after Surgery

  • Jin, Xin (Deparment of Pharmacy, Xijing Hospital, Fourth Military Medical University) ;
  • Zhang, Ke-Jin (Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University) ;
  • Guo, Xu (State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University) ;
  • Myers, Ronald (Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University) ;
  • Ye, Zhong (Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University) ;
  • Zhang, Zhi-Pei (Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University) ;
  • Li, Xiao-Fei (Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University) ;
  • Yang, Hu-Shan (Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University) ;
  • Xing, Jin-Liang (State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University)
  • Published : 2014.09.15

Abstract

Over-expression of de novo lipogenesis (DNL) genes is associated with the prognosis of various types of cancers. However, the effects of single nucleotide polymorphisms (SNPs) in these genes on recurrence and survival of non-small cell lung cancer (NSCLC) patients after surgery are still unknown. In this study, a total of 500 NSCLC patients who underwent surgery treatment were included. Eight SNPs in 3 genes (ACACA, FASN and ACLY) of the DNL pathway were examined using the Sequenom iPLEX genotyping system. Multivariate Cox proportional hazards regression and Kaplan-Meier curves were used to analyze the association of SNPs with patient survival and tumour recurrence. We found that two SNPs in the FASN gene were significantly associated with the recurrence of NSCLC. SNP rs4246444 had a significant association with lung cancer recurrence under additive model (hazard ratio [HR], 0.82; 95% confidence interval [95%CI], 0.67-1.00; p=0.05). Under the dominant model, rs4485435 exhibited a significant association with recurrence (HR, 0.75; 95%CI, 0.56-1.01; p=0.05). Additionally, SNP rs9912300 in ACLY gene was significantly associated with overall survival in lung cancer patients (HR, 1.41; 95%CI, 1.02-1.94, p=0.04) under the dominant model. Further cumulative effect analysis showed moderate dose-dependent effects of unfavorable SNPs on both survival and recurrence. Our data suggest that the SNPs in DNL genes may serve as independent prognostic markers for NSCLC patients after surgery.

Keywords

References

  1. Alo PL, Visca P, Marci A, et al (1996). Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer, 77, 474-82. https://doi.org/10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K
  2. Bauer DE, Hatzivassiliou G, Zhao F, et al (2005). ATP citrate lyase is an important component of cell growth and transformation. Oncogene, 24, 6314-22. https://doi.org/10.1038/sj.onc.1208773
  3. Blanchette M, Kent WJ, Riemer C, et al (2004). Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res, 14, 708-15. https://doi.org/10.1101/gr.1933104
  4. Cantor JR, and Sabatini DM (2012). Cancer cell metabolism: one hallmark, many faces. Cancer Discov, 2, 881-98. https://doi.org/10.1158/2159-8290.CD-12-0345
  5. Cerne D, Zitnik IP, Sok M (2010). Increased fatty acid synthase activity in non-small cell lung cancer tissue is a weaker predictor of shorter patient survival than increased lipoprotein lipase activity. Arch Med Res, 41, 405-9. https://doi.org/10.1016/j.arcmed.2010.08.007
  6. Chajes V, Cambot M, Moreau K, et al (2006). Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res, 66, 5287-94. https://doi.org/10.1158/0008-5472.CAN-05-1489
  7. De Schrijver E, Brusselmans K, Heyns W, et al (2003). RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Res, 63, 3799-804.
  8. Dinse GE, Lagakos SW (1982). Nonparametric estimation of lifetime and disease onset distributions from incomplete observations. Biometrics, 38, 921-32. https://doi.org/10.2307/2529872
  9. Dolley G, Boisclair ME, Lamarche B, et al (2011). Interactions between dietary fat intake and FASN genetic variation influence LDL peak particle diameter. J Nutrigenet Nutrige, 4, 137-45. https://doi.org/10.1159/000327778
  10. Eggert SL, Huyck KL, Somasundaram P, et al (2012). Genomewide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. Am J Hum Genet, 91, 621-8. https://doi.org/10.1016/j.ajhg.2012.08.009
  11. Flynn R (2012). Survival analysis. J Clin Nurs, 21, 2789-97. https://doi.org/10.1111/j.1365-2702.2011.04023.x
  12. Goldstraw P, Ball D, Jett JR, et al (2011). Non-small-cell lung cancer. Lancet, 378, 1727-40. https://doi.org/10.1016/S0140-6736(10)62101-0
  13. Hatzivassiliou G, Zhao F, Bauer DE, et al (2005). ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell, 8, 311-21. https://doi.org/10.1016/j.ccr.2005.09.008
  14. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA-Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  15. Kao YC, Lee SW, Lin LC, et al (2013). Fatty acid synthase overexpression confers an independent prognosticator and associates with radiation resistance in nasopharyngeal carcinoma. Tumor Biol, 34, 759-68. https://doi.org/10.1007/s13277-012-0605-y
  16. Kuhajda FP (2000). Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition, 16, 202-8. https://doi.org/10.1016/S0899-9007(99)00266-X
  17. Laing RE, Hess P, Shen Y, et al (2011). The role and impact of SNPs in pharmacogenomics and personalized medicine. Curr Drug Metab, 12, 460-86. https://doi.org/10.2174/138920011795495268
  18. Li N, Bu X, Tian X, et al (2012a). Fatty acid synthase regulates proliferation and migration of colorectal cancer cells via HER2-PI3K/Akt signaling pathway. Nutr Cancer, 64, 864-70. https://doi.org/10.1080/01635581.2012.701704
  19. Li N, Bu X, Wu P, et al (2012b). The “HER2-PI3K/Akt-FASN Axis” regulated malignant phenotype of colorectal cancer cells. Lipids, 47, 403-11. https://doi.org/10.1007/s11745-011-3649-7
  20. Lin R, Tao R, Gao X, et al (2013). Acetylation stabilizes ATPcitrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell, 51, 506-18. https://doi.org/10.1016/j.molcel.2013.07.002
  21. Liu HB, Peng YP, Dou CW, et al (2012). Comprehensive study on associations between nine SNPs and glioma risk. Asian Pac J Cancer Prev, 13, 4905-8. https://doi.org/10.7314/APJCP.2012.13.10.4905
  22. Migita T, Narita T, Nomura K, et al (2008). ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res, 68, 8547-54. https://doi.org/10.1158/0008-5472.CAN-08-1235
  23. Migita T, Ruiz S, Fornari A, et al (2009). Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst, 101, 519-32. https://doi.org/10.1093/jnci/djp030
  24. Nguyen PL, Ma J, Chavarro JE, et al (2010). Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival. J Clin Oncol, 28, 3958-64. https://doi.org/10.1200/JCO.2009.27.0793
  25. Ogino S, Nosho K, Meyerhardt JA, et al (2008). Cohort study of fatty acid synthase expression and patient survival in colon cancer. J Clin Oncol, 26, 5713-20. https://doi.org/10.1200/JCO.2008.18.2675
  26. Pizer ES, Thupari J, Han WF, et al (2000). Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fattyacid synthase inhibition in human breast cancer cells and xenografts. Cancer Res, 60, 213-8.
  27. Rahman MT, Nakayama K, Rahman M, et al (2012). Fatty acid synthase expression associated with NAC1 is a potential therapeutic target in ovarian clear cell carcinomas. Brit J Cancer, 107, 300-7. https://doi.org/10.1038/bjc.2012.246
  28. Shastry BS (2009). SNPs: impact on gene function and phenotype. Meth Mol Biol, 578, 3-22. https://doi.org/10.1007/978-1-60327-411-1_1
  29. Shurbaji MS, Kalbfleisch JH, Thurmond TS (1996). Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. Hum Pathol, 27, 917-21. https://doi.org/10.1016/S0046-8177(96)90218-X
  30. Storey JD, Taylor JE, Siegmund D (2004). Strong control, conservative point estimation and simultaneous conservative consistency of false discovery rates: a unified approach. J R Stat Soc Series B Stat Methodol, 66, 187-205. https://doi.org/10.1111/j.1467-9868.2004.00439.x
  31. Swinnen JV, Brusselmans K, Verhoeven G (2006). Increased lipogenesis in cancer cells: new players, novel targets. Curr Opin Clin Nutr, 9, 358-65. https://doi.org/10.1097/01.mco.0000232894.28674.30
  32. Wang Y, Wang Y, Shen L, et al (2012). Prognostic and therapeutic implications of increased ATP citrate lyase expression in human epithelial ovarian cancer. Oncol Rep, 27, 1156-62.
  33. Warburg O (1956). On the origin of cancer cells. Science, 123, 309-14. https://doi.org/10.1126/science.123.3191.309
  34. Xing J, Myers RE, He X, et al (2011). GWAS-identified colorectal cancer susceptibility locus associates with disease prognosis. Eur J Cancer, 47, 1699-707. https://doi.org/10.1016/j.ejca.2011.02.004
  35. Yang Y, Liu H, Li Z, et al (2011). Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers. Int J Biochem Mol Biol, 2, 89-98.
  36. Zhou F, He X, Liu H, et al (2012). Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer. Cancer, 118, 937-46. https://doi.org/10.1002/cncr.26348

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