脂肪酸合成通路关键基因ACLY遗传变异参与肝癌恶性进展的作用机制研究

Liver cancer is one of the most common malignant tumors in China. Clinically we often find that even though the same pathological type, the same stage, using the same treatment strategys for the Liver cancer patients, the prognosis are still showed significant differences. The reason for this different outcome may be related to the genetic background for each patients- - genetic polymorphisms (such as single nucleotide polymorphisms,SNPs). Screening and identification of tumor markers that used to effectively predict liver cancer prognosis are the key and the premise of personalized medicine for HCC. De novo Fatty acids synthesis has been widely found in many human tumors, the expression of the key genes in this pathway has been reported in various human tumors, and these genes were strongly associated with the tumorgenesis and development of tumors. However,there is no study report to date for the association of SNPs in the key genes of fatty acid synthesis pathway and liver cancer prognosis.Our preliminary work find out that the different alleles of the functional SNP rs2304497,which is located in the ACLY,the key gene of fatty acid synthesis pathway,is significantly associated with the progression of the liver cancer.Based on this detection, this project intends to investigate the deep mechanism of the different alleles of SNP rs2304497 affect the ACLY enzyme and fatty acid synthesis through cellular and tissue levels,thus to clarify the mechanism that genetic variation of SNP rs2304497 affect the progression of liver cancer. The launching of this project has a important meaning for the in-depth understanding of the mechanism that the functional SNP in the key genes of fatty acid synthesis pathway is associated with the liver cancer prognosis, and guiding the personalized medicine of the patients with liver cancer.

肝癌是我国最常见的恶性肿瘤之一，临床上经常发现同一病理类型、分期或采用相同治疗方案的肝癌患者预后仍存在显著差异。造成这种预后差异的原因,可能与肝癌患者自身的遗传背景- - 遗传多态性（SNP）相关。脂肪酸合成异常普遍发生于人类多种肿瘤，该通路关键基因的表达与肿瘤的发生及进展显著相关。然而，迄今为止对脂肪酸合成通路关键基因的SNPs与肝癌预后的相关性研究尚无报道。本项目前期工作发现脂肪酸合成通路关键基因ACLY功能性SNP位点rs2304497不同基因型与肝癌恶性进展显著相关。基于前期发现，本项目拟从细胞水平和组织水平，研究rs2304497不同基因型影响脂肪酸合成以及ACLY酶自身功能的机制，进而阐明rs2304497不同基因型影响肝癌恶性进展的具体机理。本项目的开展对于深入理解脂肪酸合成通路关键基因的SNP影响肝癌预后的作用机制，指导肝癌患者的个体化医疗具有重要的指导意义。

肝癌是我国最常见的恶性肿瘤之一，临床上经常发现同一病理类型、同一分期、采用相同治疗方案的肝癌患者预后仍存在显著差异。造成这种预后差异的原因,可能与肝癌患者自身的遗传背景——遗传多态性（SNP）相关。脂肪酸合成普遍发生于人类多种肿瘤，该通路关键基因的表达与肿瘤的发生及进展显著相关。然而，迄今为止对脂肪酸合成通路关键基因的SNPs与肝癌预后的相关性研究尚无报道。.本项目利用sequenom基因质谱仪完成492例肝癌手术患者以及419例肝癌介入患者9个脂肪酸合成通路关键基因SNP分型检测，结合患者的临床资料及随访资料，采用生物信息学及统计学方法分析，全面系统的研究脂肪酸合成通路关键基因的遗传多态性（SNP）与肝癌患者预后的关系，并通过细胞及组织进行相关功能研究。通过分析发现，ACACA基因SNP位点rs7211875与rs11871275不同基因型与肝癌手术患者死亡风险密切相关，同时rs11871275及FASN基因SNP位点rs4485435不同基因型与肝癌手术患者复发风险密切相关。并且三个SNP位点危害基因型对肝癌手术患者预后具有累积效应。功能实验发现，rs11871275不同基因型患者ACACA基因表达水平存在差异，从而影响预后。分析419例肝癌介入患者基因分型结果与患者预后，发现在AFP水平较低的患者组中， ACLY基因SNP位点rs9912300不同基因型与肝癌介入患者预后密切相关，而在AFP水平较高的患者组中， ACACA基因SNP位点rs11871275不同基因型与患者预后相关。交互作用分析发现，两个SNP位点均与患者AFP水平高低存在交互作用，可联合进行预后指导。.本项目的开展对于深入理解脂肪酸合成通路关键基因的SNP对肝癌预后的预测能力，指导肝癌患者的个体化医疗，提高疗效及生存率具有重要的指导意义。下一步计划将重点关注脂肪酸合成通路关键基因SNP影响肝癌预后的具体功能机制，为进一步的临床转化奠定理论基础。