基于加权基因共表达网络的急性髓系白血病预后基因筛选-现代医学

基于加权基因共表达网络的急性髓系白血病预后基因筛选

作者：高玥¹ 2 张行³ 陈远方² 4 杨一洲² 4 韩磊¹ 5 朱宝立² 5 徐酩² 4 5

单位：1. 江苏省疾病预防控制中心职业病防治所, 江苏南京 210009;
2. 江苏省卫生应急工程研究中心, 江苏南京 210009;
3. 鼓楼区疾病预防控制中心, 江苏南京 210003;
4. 江苏省疾病预防控制中心卫生应急工程研究中心, 江苏南京 210009;
5. 南京医科大学公共卫生

关键词：急性髓系白血病加权基因共表达网络蛋白磷酸酶Mg²⁺/Mn²⁺依赖性1J 生存率

分类号：R733.71

出版年·卷·期（页码）：2025·44·第六期（883-892）

摘要：

目的： 本研究旨在利用加权基因共表达网络分析(WGCNA)挖掘与急性髓系白血病(AML)基因表达谱中生存相关的基因，并分析其与AML患者生存预后的关系。方法： 从癌症基因组图谱(TCGA)数据库下载AML患者基因表达和临床数据并进行预处理。利用R语言中WGCNA包对AML表达谱数据构建加权基因共表达网络，筛选与AML生存相关的基因模块，并进一步建立Cox比例风险模型鉴定模块中生存相关的关键基因(hub gene)。时间依赖性受试者工作特征(ROC)曲线分析预后模型的预测能力，并建立诺莫图(Nomogram)进行1年、3年和5年生存预测。结果： 根据基因表达的相关性及WGCNA分析，共发现22个基因模块。其中Grey60基因模块与AML生存有显著的正相关性(Cox=0.27，P<0.001)，通过生存分析筛选模块内生存相关的基因共5个：前T细胞抗原受体α(PTCRA)、溶质载体家族4成员3(SLC4A3))、丝氨酸蛋白酶抑制剂家族F成员1(SERPINF1)、蛋白磷酸酶Mg²⁺/Mn²⁺依赖性1J (PPM1J)、肌红蛋白(MB)，并从中挑选PPM1J作为hub gene。Cox回归模型森林图显示C-index=0.71,P<0.001。同时，PPM1J高表达组的死亡风险是低表达组的2.83倍，且不同年龄和细胞遗传学风险类型的AML患者生存率差异均有统计学意义(P<0.05)。Nomogram图显示PPM1J低表达组患者的1、3和5年预测生存率分别为>85%、>85%和>70%，而PPM1J高表达组患者的1、3、5年生存率分别为65%、35%、20%。结论： PPM1J基因在AML中的高表达可能与AML患者预后不良有关，可作为AML预后的潜在生物标志物及治疗靶点。

Objective: To identify survival-associated genes in acute myeloid leukemia(AML) through weighted gene co-expression network analysis(WGCNA) and investigate their prognostic significance. Methods: Gene expression profiles and clinical data of AML patients were obtained from the Cancer Genome Atlas(TCGA) database. After data preprocessing(normalization, variance filtering, and outlier removal), the WGCNA package in R was employed to construct a weighted gene co-expression network. Survival-associated gene modules were identified, followed by Cox proportional hazards modeling to determine hub genes. Time-dependent receiver operating characteristic(ROC) curves were used to evaluate predictive performance, and a nomogram was established for 1, 3, and 5 year survival probability prediction.Results: WGCNA analysis identified 22 gene modules. The Grey60 module showed significant positive correlation with AML survival(Cox=0.27, P<0.001). Five survival-related genes were identified: pre-T cell antigen receptor α(PTCRA), solute carrier family 4 member 3(SLC4A3), serine protease inhibitor family F member 1(SERPINF1), protein phosphatase Mg²⁺/Mn²⁺-dependent 1J(PPM1J), and myoglobin(MB). PPM1J was selected as the hub gene based on the largest area under ROC curve. Multivariate Cox regression forest plot analysis C-index=0.71(P<0.001) revealed a 2.83-fold higher mortality risk in the PPM1J high-expression group compared to the low-expression group. Significant survival differences were observed among AML patients with different ages and cytogenetic risk types(P<0.05). The Nomogram predicted 1, 3, and 5 year survival rates of >85%, >85%, and >70% respectively for the PPM1J low-expression group, compared to 65%, 35%, and 20% for the high-expression group. Conclusion: High expression of PPM1J is associated with poor prognosis in AML, suggesting its dual potential as both a prognostic biomarker and therapeutic target.

参考文献：

[1] MEDEIROS B C.Is there a standard of care for relapsed AML?[J].Best Pract Res Clin Haematol,2018,31(4):384-386.
[2] DESCHLER B,LUBBERT M.Acute myeloid leukemia:epidemiology and etiology[J].Cancer,2006,107(9):2099-2107.
[3] SIEGEL R L,MILLER K D,FUCHS H E,et al.Cancer Statistics,2021[J].CA Cancer J Clin,2021,71(1):7-33.
[4] 董谦,龚娜英,陈康,等.急性髓系白血病潜在关键基因表达谱的生物信息学分析[J].检验医学与临床,2021,18(13):1828-1832.
[5] 方芳,朱平.基因表达谱分析有望改善白血病的治疗[J].中国实验血液学杂志,2014,22(6):1735-1738.
[6] XU P,YANG J,LIU J,et al.Identification of glioblastoma gene prognosis modules based on weighted gene co-expression network analysis[J].BMC Med Genomics,2018,11(1):96.
[7] 刘伟,李立,叶桦,等.权重基因共表达网络分析在生物医学中的应用[J].生物工程学报,2017,33(11):1791-1801.
[8] BHONSLE S P,ARENA C B,SWEENEY D C,et al.Mitigation of impedance changes due to electroporation therapy using bursts of high-frequency bipolar pulses[J].Biomed Eng Online,2015,14 Suppl 3(Suppl 3):S3.
[9] ZHANG B,HORVATH S.A general framework for weighted gene co-expression network analysis[J].Stat Appl Genet Mol Biol,2005,4:Article 17.
[10] HORVATH S,DONG J.Geometric interpretation of gene coexpression network analysis[J].PLoS Comput Biol,2008,4(8):e1000117.
[11] 智鹏.基于临床生物信息学筛选急性髓系白血病预后标志物[D].山西:山西医科大学,2022.
[12] 王敏.加权基因共表达网络分析挖掘急性髓系白血病相关致病基因[D].杭州：浙江大学,2019.
[13] 钱婷,李小杉,王文静,等.动脉性肺动脉高压特异性差异表达基因的筛选及生物信息学分析[J].现代医学,2023,51(12):1697-1704.
[14] KAMADA R,KUDOH F,ITO S,et al.Metal-dependent Ser/Thr protein phosphatase PPM family:evolution,structures,diseases and inhibitors[J].Pharmacol Ther,2020,215:107622.
[15] WHISENANT T C,HO D T,BENZ R W,et al.Computational prediction and experimental verification of new MAP kinase docking sites and substrates including Gli transcription factors[J].PLoS Comput Biol,2010,6(8):e1000908.
[16] LI M,LI Y,WEEKS O,et al.SOS2 and ACP1 loci identified through large-scale exome chip analysis regulate kidney development and function[J].J Am Soc Nephrol,2017,28(3):981-994.
[17] AVRUCH J.MAP kinase pathways:the first twenty years[J].Biochim Biophys Acta,2007,1773(8):1150-1160.
[18] YAN H,QU J,CAO W,et al.Identification of prognostic genes in the acute myeloid leukemia immune microenvironment based on TCGA data analysis[J].Cancer Immunol Immunother,2019,68(12):1971-1978.
[19] SMELTY P,MARCHAL C,RENARD R,et al.Identification of the pre-T-cell receptor alpha chain in nonmammalian vertebrates challenges the structure-function of the molecule[J].Proc Natl Acad Sci U S A,2010,107(46):19991-19996.
[20] MINGUENEAU M,KRESLAVSKY T,GRAY D,et al.The transcriptional landscape of alphabeta T cell differentiation[J].Nat Immunol,2013,14(6):619-632.
[21] CHAPIRO E,DELABESSE E,ASNAFI V,et al.Expression of T-lineage-affiliated transcripts and TCR rearrangements in acute promyelocytic leukemia:implications for the cellular target of t(15;17)[J].Blood,2006,108(10):3484-3493.
[22] LAVROV A V,CHELYSHEVA E Y,SMIRNIKHINA S A,et al.Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia[J].BMC Genet,2016,17 Suppl 1(Suppl 1):14.
[23] LINSER P J,SMITH K E,SERON T J,et al.Carbonic anhydrases and anion transport in mosquito midgut pH regulation[J].J Exp Biol,2009,212(Pt 11):1662-1671.
[24] MIAO T W,DU L Y,XIAO W,et al.Identification of survival-associated gene signature in lung cancer coexisting with COPD[J].Front Oncol,2021,11:600243.
[25] BECKER J,SEMLER O,GILISSEN C,et al.Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta[J].Am J Hum Genet,2011,88(3):362-371.
[26] ZHANG C,YANG W,ZHANG S,et al.Pan-cancer analysis of osteogenesis imperfecta causing gene SERPINF1[J].Intractable Rare Dis Res,2022,11(1):15-24.
[27] 胡昕滢,栾洁.色素上皮衍生因子在人晶状体上皮细胞中的表达[J].东南大学学报(医学版),2019,38(2):343-346.
[28] FARGE T,SALAND E,DE TONI F,et al.Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism[J].Cancer Discov,2017,7(7):716-735.

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