目的: 通过生物信息学方法,探究FAM25A对胰腺癌的诊断、预后价值,分析其与免疫浸润相关性,并对该基因在胰腺癌中发生发展的潜在作用机制进行阐述。方法: 从TCGA、GTEx和GEO数据库获取胰腺癌数据集,Rstudio用于数据分析和可视化。明确FAM25A的表达差异,采用K-M分析FAM25A的表达与胰腺癌总生存时间的关系,Cox回归分析FAM25A表达与胰腺癌预后因素的相关性,分析FAM25A表达与免疫细胞浸润的相关性。根据WGCNA将与FAM25A和肿瘤纯度最相关的模块基因导入STRING构建PPI网络并获取GO和KEGG,采用GSEA分析FAM25A高低表达的富集通路,利用Cytoscape中MOCDE聚类子网络获取显著相关的节点,综合以上信息分析FAM25A在胰腺癌中的潜在机制。结果: 差异分析提示FAM25A在胰腺癌中高表达具有统计学意义(P<0.01);K-M分析结果显示FAM25A高表达患者的生存期明显短于低表达患者;对胰腺癌预后相关因素进行Cox回归分析,结果提示FAM25A为胰腺癌的独立危险因素(HR=2.4, 95%CI=1.614-3.592);免疫细胞浸润相关性分析显示FAM25A可以降低T淋巴细胞水平;GO、KEGG、GSEA和MCODE结果表明FAM25A主要在细胞与细胞间相互作用、细胞间信号产生与转导、趋化因子及免疫反应等相关途径中发挥作用 。结论: FAM25A在胰腺癌中过表达是胰腺癌一个独立的不良预后因子,FAM25A异常表达可以作为胰腺癌诊断和判断预后的生物标志物,其生物学效应可能是通过促进胰腺癌的增殖、侵袭和转移实现的。
Objective: To explore the diagnostic and prognostic value of FAM25A in pancreatic cancer by bioinformatics methods, analyze its correlation with immune infiltration, and elaborate the potential mechanism of FAM25A in the occurrence and development of pancreatic cancer. Methods: The Pancreatic cancer datasets were obtained from TCGA, GTEx and GEO databases, and Rstudio was used for data analysis and visualization. The expression difference of FAM25A was clarified. The relationship between the expression of FAM25A and the overall survival time of pancreatic cancer was analyzed by K-M. The correlation between FAM25 A expression and prognostic factors of pancreatic cancer was analyzed by Cox regression. The correlation between FAM25A expression and immune cell infiltration was analyzed. According to WGCNA, the module genes most related to FAM25A and tumor purity were imported into STRING to construct PPI network and obtain GO and KEGG. GSEA was used to analyze the enrichment pathway of high and low expression of FAM25A, and MOCDE clustering subnetwork in Cytoscape was used to obtain significantly related nodes. Based on the above information, the potential mechanism of FAM25A in pancreatic cancer was analyzed. Results: The results showed that FAM25A was significantly more highly expressed in pancreatic cancer (P<0.01); K-M analysis showed that the survival time of patients with high expression of FAM25 A was significantly shorter than that of patients with low expression; Cox regression analysis of prognostic factors related to pancreatic cancer suggested that FAM25A was an independent risk factor for pancreatic cancer (HR=2.4, 95%CI=1.614-3.592); Correlation analysis of immune cell infiltration showed that FAM25A could reduce T lymphocyte level; GO, KEGG, GSEA and MCODE results showed that FAM25A mainly played a role in cell-cell interaction, intercellular signal generation and transduction, chemokine and immune response. Conclusion: FAM25A over-expression in pancreatic cancer is an independent poor prognostic factor in pancreatic cancer. Abnormal expression of FAM25A can also be used as bio-markers for diagnosis and prognosis of pancreatic cancer. Its biological effects may be achieved by promoting proliferation, invasion and metastasis of pancreatic cancer.
[1] Hammel P, Kindler HL, Reni M, et al. Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib[J]. Ann Oncol, 2019,30(12):1959-1968.
[2] Klein AP, Wolpin BM, Risch HA, et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer[J]. Nat Commun, 2018,9(1):556.
[3] Chen-Zhao X, Hernando O, Lópezm, et al. A prospective observational study of the clinical and pathological impact of stereotactic body radiotherapy (SBRT) as a neoadjuvant strategy of chemoradiation in pancreatic cancer[J]. Clin Transl Oncol, 2020,22(9):1499-1505.
[4] 中华医学会肿瘤学分会. 胰腺癌早诊早治专家共识[J].临床肝胆病志, 2020, 36(12): 2675-2680.
[5] Deloukas P, Earthrowl ME, Grafham DV, et al. The DNA sequence and comparative analysis of human chromosome 10[J]. Nature, 2004,429(6990):375-381.
[6] Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2[J]. Genome Biol, 2014,15(12):550.
[7] Vivian J, Rao AA, Nothaft FA, et al. Toil enables reproducible, open source, big biomedical data analyses[J]. Nat Biotechnol, 2017,35(4):314-316.
[8] Liu JF, Lichtenberg T, Hoadley KA, et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics[J]. Cell, 2018,173(2):400-416.
[9] Bindea G, Mlecnik B, Tosolini M, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer[J]. Immunity, 2013,39(4):782-795.
[10] Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis[J]. BMC Bioinformatics, 2008,9:559.
[11] Szklarczyk D, Gable AL, Lyon D, et al. STRING v11:protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets[J]. Nucleic Acids Res, 2019,47(1):607-613.
[12] Yu GC, Wang LG, Han YY, et al. clusterProfiler: an R package for comparing biological themes among gene clusters[J]. OMICS, 2012,16(5):284-287.
[13] Anger F, Lock JF, Klein I, et al. Does concurrent cholestasis alter the prognostic value of preoperatively elevated CA19-9 serum levels in patients with pancreatic head adenocarcinoma?[J]. Ann Surg Oncol, 2022,29(13):8523-8533.
[14] Ali-Khan A, Liu XH, Yan XL, et al. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression[J]. Cancer Metastasis Rev, 2021,40(1):245-272.
[15] Lee DY, Hah JH, Jeong WJ, et al. The expression of defensin-associated genes may be correlated with lymph node metastasis of early-stage tongue cancer[J]. Clin Exp Otorhinolaryngol, 2022,15(4):372-379.
[16] 章洪鹏,汤东,王道荣. 胰腺星状细胞与肿瘤细胞相互作用的研究进展[J]. 国际外科学杂志,2018,45(9):641-644.
[17] Yang J, Jin L, Kim HS, et al. KDM6A loss recruits tumor-associated neutrophils and promotes neutrophil extracellular trap formation in pancreatic cancer[J]. Cancer Res, 2022,82(22):4247-4260.
[18] 王宇鹏,李彩霞,张淑坤. CC亚族趋化因子配体20与胰腺癌[J]. 中国中西医结合外科杂志,2017,23(1):101-103.
[19] Makarov AA, Zou J, Houston DR, et al. Lamin A molecular compression and sliding as mechanisms behind nucleoskeleton elasticity[J]. Nat Commun, 2019,10(1):3056.
[20] Dos-Santos G, Rogel MR, Baker MA, et al. Vimentin regulates activation of the NLRP3 inflammasome[J]. Nat Commun, 2015,6:6574.
[21] Holle AW, Kalafat M, Ramos AS, et al. Intermediate filament reorganization dynamically influences cancer cell alignment and migration[J]. Sci Rep, 2017,7:45152.
[22] Lin X, Ye LY, Wang X, et al. Follicular helper T cells remodel the immune microenvironment of pancreatic cancer via secreting CXCL13 and IL-21[J]. Cancers, 2021,13(15):3678.
[23] Fan XZ, Alekseyenko AV, Wu J, et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study[J]. Gut, 2018,67(1):120-127.