脂肪酸转运基因对乳腺癌临床病理特征及预后预测数据库资料分析

Prediction of correlations between fatty acid transport genes and clinicopathological features and prognosis of breast cancer based on database

目的肿瘤细胞为了满足其快速生长和增殖的能量需求,通常表现出以脂肪生成及摄取增加为主要特征的代谢改变。在包括乳腺癌在内许多癌症中,疾病恶化的一个重要原因是脂肪酸代谢失调。脂肪酸转运途径在乳腺癌中少有研究。本项研究旨在通过评估脂肪酸转运途径上基因表达量的改变,分析其与乳腺癌临床病理特征及预后的关联。方法共纳入肿瘤基因组计划数据库(the Cancer Genome Atlas Database,TCGA)中1 078例女性乳腺癌患者。分析脂肪酸转运基因在乳腺正常组织和肿瘤组织之间表达量的差异,以及脂肪酸转运基因表达量与乳腺癌临床病理特征的关联。Cox比例风险回归模型进行单因素和多因素生存预后分析。Kaplan-Meier生存曲线分析每个基因与乳腺癌患者总体生存(overall survival,OS)关联性,比较生存曲线之间的差异。用Oncomine数据库中脂肪酸转运基因表达数据验证TCGA中差异分析结果。结果通过对TCGA数据库中脂肪酸转运基因表达量的分析,发现溶质载体家族27成员4(solute carrier family 27member 4,SLC27A4)在乳腺癌中的表达量高于其邻近乳腺正常组织(t=9.201,P<0.001),这一点在Oncomine数据库中也得到了证实;同时其表达量的高低与肿瘤分期(χ~2=6.901,P=0.009)、淋巴结转移(χ^2=10.774,P=0.001)、雌激素受体(estrogen receptor,ER)状态(χ^2=13.754,P<0.001)及人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)状态(χ~2=1.684,P=0.002)存在关联。脂肪酸移位酶(fatty acid translocase,CD36)表达量与乳腺癌肿瘤分期(χ^2=8.121,P=0.004)、淋巴结转移(χ^2=3.932,P=0.047)及ER状态(χ^2=2.030,P<0.001)有关联,还与肿瘤大小(χ^2=4.005,P=0.045)、切缘状态(χ^2=6.896,P=0.032)及孕激素受体(progesterone receptor,PR)状态(χ~2=13.244,P<0.001)有关联。生存分析发现,SLC27A4(χ^2=4.151,P=0.042)和CD36(χ^2=5.121,P=0.024)高表达预示更短的OS;并且SLC27A4与CD36同时高表达患者的OS也更差,χ^2=4.465,P=0.035。结论脂肪酸转运通路上SLC27A4和CD36的表达与乳腺癌肿瘤分期高、淋巴结转移及预后差之间存在关联;从而为将来脂肪酸转运基因作为乳腺癌新型的预后标志物和潜在的治疗靶标提供了初步证据。

OBJECTIVE Cancer cells exhibit metabolic alterations characterized by increased lipogenesis and uptake,which satisfies the energy demand to facilitate their rapid growth and proliferation.Dysregulation of fatty acid metabolism is recognized as an important reason of malignant transformation in many different cancers,including breast cancer.Fatty acid transport pathway is rarely studied in breast cancer.This study aimed to evaluate genetic alterations in the fatty acid transport pathway to illustrate its association with clinicopathological features and outcome in breast cancer.METHODS A total of 1078 female breast cancer patients were included in our study from the Cancer Genome Atlas(TCGA)database.The differences in the expression of fatty acid transport genes(FATGs)between normal and tumor tissues,as well as the correlations between the FATGs expression and clinicopathological features of breast cancer were analyzed.Cox proportional hazards model was used to estimate univariate and multivariate hazard ratios and 95%confidence intervals.Based on the Kaplan-Meier method and Log-rank test,survival analysis was done to identify the correlation between each FATG and overall survival(OS).The expression data of FATGs in the Oncomine database was used to verify the results of the differential analysis in TCGA.RESULTS We demonstrated that SLC27A4(t=9.201,P<0.001)exhibited elevated expression in breast cancer than adjacent normal tissues in TCGA database as well as in Oncomine database.The TNM stage(χ^2=6.901,P=0.009),N stage(χ^2=10.774,P=0.001),estrogen receptor(ER)status(χ^2=13.754,P<0.001)and human epidermal growth factor receptor 2(HER2)status(χ^2=1.684,P=0.002)were significantly related to the expression of SLC27 A4.CD36 expression revealed correlation with the TNM stage(χ^2=8.121,P=0.004),T stage(χ^2=4.005,P=0.045),N stage(χ^2=3.932,P=0.047),margin status(χ^2=6.896,P=0.032),ER status(χ^2=2.030,P<0.001)and progesterone receptor(PR)status(χ^2=13.244,P<0.001).Notably,increased expression of SLC27A4 or CD36 displayed a short OS(χ^2=4.151,P=0.042;χ^2=5.121,P=0.024).Patients with high co-expression of SLC27A4 and CD36 had poor survival rates(χ^2=4.465,P=0.035).CONCLUSIONS Expression of SLC27A4 and CD36 was significantly associated with lymph node metastasis,high tumor stage and poor outcome in breast cancer.This study provided preliminary evidence that FATGs could serve as a novel prognostic marker and a potential therapeutic target for breast cancer.