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.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for 80% of all types of lung cancer (Jemal et al, 2011)
We found that two Single nucleotide polymorphism (SNP) in the fatty-acid synthase (FASN) gene were significantly associated with the recurrence of NSCLC
We evaluated the effects of eight functional SNPs in three genes (ACACA, FASN, and ATP citrate lyase (ACLY)) of de novo lipogenesis (DNL) pathway on the prognosis of NSCLC patients
Summary
Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for 80% of all types of lung cancer (Jemal et al, 2011). Most of the glycolytic endproduct, pyruvate, is converted to lactate, whereas some is converted to acetyl-CoA that is in turn used for de novo fatty-acid synthesis, termed de novo lipogenesis (DNL) (Swinnen et al, 2006). Proliferating cancer cells need to synthesize fatty acids de novo to continually provide lipids for energy production, cell membrane regeneration and lipid modification of protein. Fatty acids and their derivatives are important signaling molecules that may affect many fundamental cell processes, including cellular survival, proliferation, migration, invasion, angiogenesis and therapy resistance. DNL involves three rate-limiting enzymes, i.e. ATP citrate lyase (ACLY), acetyl-CoA carboxylase α (ACACA) and fatty-acid synthase (FASN). DNL is commonly elevated and the supply of cellular fatty acid is highly dependent on the de novo synthesis. Deregulated de novo fatty-acid synthesis directly leads to cellular fatty-acid accumulation and affects fundamental cellular processes, including
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