Journal of Shandong University (Health Sciences) ›› 2022, Vol. 60 ›› Issue (3): 51-58.doi: 10.6040/j.issn.1671-7554.0.2021.0821

Previous Articles    

A prognostic risk model for LKB1 mutant lung adenocarcinoma based on aberrant DNA methylation sites

ZHENG Haotian1*, WANG Guanghui1,2*, ZHAO Xiaogang3, WANG Yadong1, ZENG Yukai1, DU Jiajun1,2   

  1. 1. Institute of Oncology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China;
    2. Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China;
    3. Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China
  • Published:2022-03-09

PDF (PC)

107

Abstract: Objective To construct a methylation-related prognostic risk model of liver kinase B1(LKB1)mutant lung adenocarcinoma. Methods The RNA and methylation sequencing data from the The Cancer Genome Atlas(TCGA)database were downloaded and analyzed. Differentially expressed genes that significantly affected the prognosis and were regulated by different methylation sites were screened out to construct a prognostic risk model. Then, the LKB1 mutant lung adenocarcinoma patients were divided into the high-risk group and low-risk group and the corresponding function was analyzed. Results Three prognostic-related genes with low methylation levels and high expression levels were screened out and a prognostic risk model of LKB1 mutant lung adenocarcinoma was constructed. Multivariate COX regression analysis showed that Risk score could be used as an independent predictor(HR>2, P<0.001). The receiver operating characteristic(ROC)curve confirmed that the Risk score had better survival predictive ability than other clinicopathological characteristics. The cancer-promoting pathway was activated in the high-risk group and the degree of immune cell infiltration was significantly higher than that in the low-risk group. Conclusion Three biomarkers due to aberrant methylation are discovered in LKB1 mutant lung adenocarcinomas. The prognostic risk model can accurately screen the high-risk population among patients with LKB1 mutant lung adenocarcinoma, and provides accurate survival predictions. The study provides new ideas for the molecular mechanism and the clinical prognosis analysis of LKB1 mutant lung adenocarcinoma.

Key words: Liver kinase B1, Lung adenocarcinoma, DNA methylation, Prognostic risk model, The Cancer Genome Atlas

CLC Number: 

  • R574
[1] Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies and new targeted treatments [J]. The Lancet, 2017, 389(10066): 299-311.
[2] Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies [J]. Cancer Discov, 2017, 7(6): 596-609.
[3] Yang Z, Liu B, Lin T, et al. Multiomics analysis on DNA methylation and the expression of both messenger RNA and microRNA in lung adenocarcinoma [J]. J Cell Physiol, 2019, 234(5): 7579-7586.
[4] Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing [J]. N Engl J Med, 2012, 366(10): 883-892.
[5] Navin N, Kendall J, Troge J, et al. Tumour evolution inferred by single-cell sequencing [J]. Nature, 2011, 472(7341): 90-94.
[6] Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma [J]. Nature, 2014, 511(7511): 543-550.
[7] Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma [J]. Nature, 2008, 455(7216): 1069-1075.
[8] Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression [J]. Nat Rev Cancer, 2009, 9(8): 563-575.
[9] 马晴. LKB1抑制MMP1表达和肺癌细胞侵袭的分子机制 [D].天津:天津医科大学, 2016.
[10] Wu D, Gong C, Su C. Genome-wide analysis of differential DNA methylation in Silver-Russell syndrome [J]. Sci China Life Sci, 2017, 60(7): 692-699.
[11] Ferry L, Fournier A, Tsusaka T, et al. Methylation of DNA ligase 1 by G9a/GLP recruits UHRF1 to replicating DNA and regulates DNA methylation [J]. Mol Cell, 2017, 67(4): 550-565.e5.
[12] Zheng X, Zhang N, Wu HJ, et al. Estimating and accounting for tumor purity in the analysis of DNA methylation data from cancer studies [J]. Genome Biol, 2017, 18(1): 17.
[13] 谭玉娥, 刘鑫. IRF4、ELMO1、CLIP4和MSC启动子甲基化水平在胃癌早期筛查中的应用价值分析 [J]. 河北医药, 2021, 43(2): 182-186. TAN Yue, LIU Xin. Application value of IRF4, ELMO1 and CLIP4 promoter methylation levels in early screening of gastric cancer [J]. Hebei Medical Journal, 2021, 43(2): 182-186.
[14] Rajaraman P, Anderson BO, Basu P, et al. Recommendations for screening and early detection of common cancers in India [J]. The Lancet Oncology, 2015, 16(7): e352-e361.
[15] Wei JH, Haddad A, Wu KJ, et al. A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma [J]. Nat Commun, 2015, 6: 8699. doi: 10.1038/ncomms9699.
[16] Heyn H, Vidal E, Ferreira HJ, et al. Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer [J]. Genome Biol, 2016, 17: 11. doi: 10.1186/s13059-016-0879-2.
[17] 朱良宇, 孙宏瑜, 周谦, 等. 利用数据库资料分析DNA甲基化调控AC004540.4表达水平与肝细胞癌预后相关性 [J]. 中华肿瘤防治杂志, 2021, 28(3): 205-211. ZHU Liangyu, SUN Hongyu, ZHOU Qian, et al. Analysis of the relationship of DNA methylation AX004540.4 expression with prognosis of hepatocellular carcinoma with database data [J]. Chinese Journal of Cancer Prevention and Treatment, 2021, 28(3): 205-211.
[18] Fang Q, Chen H. Development of a novel autophagy-related prognostic signature and nomogram for hepatocellular carcinoma [J]. Front Oncol, 2020, 10: 591356. doi: 10.3389/fonc.2020.591356. eCollection 2020.
[19] Li X, Jin F, Li Y. A novel autophagy-related lncRNA prognostic risk model for breast cancer [J]. J Cell Mol Med, 2021, 25(1): 4-14.
[20] Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression [J]. Cancer Research, 2019, 79(18): 4557-4566.
[21] Pitt JM, Marabelle A, Eggermont A, et al. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy [J]. Ann Oncol, 2016, 27(8): 1482-1492.
[22] Xu JY, Zhang C, Wang X, et al. Integrative proteomic characterization of human lung adenocarcinoma [J]. Cell, 2020, 182(1): 245-261.e17.
[23] Saito M, Suzuki H, Kono K, et al. Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy [J]. Surg Today, 2018, 48(1): 1-8.
[24] 高向征, 梁可莹, 梅圣圣, 等. 联合靶向免疫检查点CD47与PDL1的抗肿瘤研究进展 [J]. 中国细胞生物学学报, 2021, 43(4): 896-904. GAO Xiangzheng, LIANG Keying, MEI Shengsheng, et al. Anti-tumor progress on dual blockage of immune checkpoints CD47 and PDL1 [J]. Chinese Journal of Cell Biology, 2021, 43(4): 896-904.
[25] Cha YJ, Kim HR, Lee CY, et al. Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status [J]. Lung Cancer, 2016, 97: 73-80. doi: 10.1016/j.lungcan.2016.05.001.
[26] Teglasi V, Reiniger L, Fabian K, et al. Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis [J]. Neuro Oncol, 2017, 19(8): 1058-1067.
[27] Thakur C, Chen F. Connections between metabolism and epigenetics in cancers [J]. Semin Cancer Biol, 2019, 57: 52-58. doi: 10.1016/j.semcancer.2019.06.006.
[28] Liu X, Fu J, Bi H, et al. DNA methylation of SFRP1, SFRP2, and WIF1 and prognosis of postoperative colorectal cancer patients [J]. BMC Cancer, 2019, 19(1): 1212.
[29] Liu P, Shen JK, Hornicek FJ, et al. Wnt inhibitory factor 1(WIF1)methylation and its association with clinical prognosis in patients with chondrosarcoma [J]. Sci Rep, 2017, 7(1): 1580.
[30] Stewart DJ. Wnt signaling pathway in non-small cell lung cancer [J]. J Natl Cancer Inst, 2014, 106(1): djt356.
[31] Marjanovic I, Karan-Djurasevic T, Kostic T, et al. Prognostic significance of combined BAALC and MN1 gene expression level in acute myeloid leukemia with normal karyotype [J]. Int J Lab Hematol, 2021, 43(3): 433-440.
[32] Hagag AA, Elshehaby WA, Hablas NM, et al. Role of BAALC gene in prognosis of acute lymphoblastic leukemia in Egyptian children [J]. Indian J Hematol Blood Transfus, 2018, 34(1): 54-61.
[33] Morita K, Masamoto Y, Kataoka K, et al. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4 [J]. Leukemia, 2015, 29(11): 2248-2256.
[34] Zhang H, Wang Y, Zhang W, et al. BAALC-AS1/G3BP2/c-Myc feedback loop promotes cell proliferation in esophageal squamous cell carcinoma [J]. Cancer Commun(Lond), 2021, 41(3): 240-257.
[35] Zhang Y, Tang B, Song J, et al. Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression [J]. J Exp Clin Cancer Res, 2019, 38(1): 92.
[36] Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer [J]. Nat Rev Drug Discov, 2018, 17(12): 887-904.
[37] Di Vito C, Mikulak J, Zaghi E, et al. NK cells to cure cancer [J]. Semin Immunol, 2019, 41: 101272. doi: 10.1016/j.smim.2019.03.004.
[38] Thommen DS, Schumacher TN. T cell dysfunction in cancer [J]. Cancer Cell, 2018, 33(4): 547-562.
[1] Bing LUO. Impact of EBV on the epigenetics of gastric carcinoma [J]. Journal of Shandong University (Health Sciences), 2021, 59(5): 30-39.
[2] CHAI Xiaoxue, YE Hui, LYU Xinran, DING Xuchao, ZHEN Qiulai, DU Juan, CAO Lili. Prognostic value of POU4F3 in 118 patients with lung adenocarcinoma and its effect on migration of lung adenocarcinoma cells [J]. Journal of Shandong University (Health Sciences), 2021, 59(11): 8-18.
[3] PANG Zhaofei, LIU Yong, ZHAO Xiaogang, YAN Tao, CHEN Xiaowei, DU Jiajun. Construction of a stemness-based scoring model predicting the efficacy of immunotherapy in lung adenocarcinoma based on public databases [J]. Journal of Shandong University (Health Sciences), 2021, 59(11): 19-28.
[4] TANG Xi, HU Ya, XU Yanhua, WANG Chunlin, QIU Ping, WANG Xianghui. MiR- 498 inhibits A549 cells EMT by targeting FOXM1 [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(4): 39-43.
[5] ZHANG Zhihui, WANG Lili, GAO Hua, ZHANG Jian, LI Juan, LI Yuan, WU Chunxiao, LU Zhiming. Role of hypoxia-inducible factor-1α in the regulation of programmed death ligand 1 expression in lung adenocarcinoma [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(4): 65-70.
[6] ZHOU Xue, WANG Yanrong, TIAN Long, MA Lianghong, YAN Bei, TIAN Jia, ZHANG Fan, ZHOU Yue, WANG Hongyan. DNA methylation and expression of SNRPN and GRB10 imprinted genes in human semen freezing-thawing process [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(1): 54-59.
[7] SUN Jie, MU Xiaoyan, DONG Xueli. Combinational and sequential effect of sunitinib and gemcitabine on K-RAS mutant A549 cells [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(3): 45-49.
[8] XU Jia, SONG Qiang. Deletion of the RASSF1A gene and promoter methylation in the bone marrow of patients with myelodysplastic syndromes [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2013, 51(2): 65-69.
[9] DONG Xue-li, MU Xiao-yan, LIU Qing-liang, SUN Jie. Effects of erlotinib combined with celecoxib on growth and angiogenesis of human lung cancer xenograft model [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2013, 51(2): 49-52.
[10] CHEN Hai-yan, YAO Shu-zhe, ZHANG Xiao-ying, ZHANG Jian-ping, ZHANG Cui-juan, ZHANG Ting-guo. Effect of the methylation of SOCS-3 and 3-OST-2 genes in endometrial cancer and its clinical pathological significances [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2013, 51(06): 75-80.
[11] FAN Heng-jian, ZHANG Yu-ke, XIAO Wei, ZHANG Yi, LI Hai-jun, WANG De-xiang. Changes of Treg and Th17 cells in the peripheral bloods of patients with
lung adenocarcinoma and their prognostic significance [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2012, 50(9): 73-78.
[12] MA Yu-hua1,2, ZHENG Yan3, JIA Yan-fei3, WANG Yun-shan3. GFR and DEC1 protein co-expression promotes lymph node
metastasis in lung adenocarcinoma [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2012, 50(3): 24-28.
[13] GUO Xiao-yu1, JIANG Yan2, XING Zhao-quan3, GUO Zhao-xin3, FANG Zhi-qing3, LIU Zhao-xu1,3. The effect of methyltransferase inhibitor on the expression of
XAF1 mRNA in prostate cancer [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2012, 50(12): 94-.
[14] LI Haijun, XIAO Wei. Increased frequency of Th17 cells in the peripheral blood of patients  with lung adenocarcinoma and its clinical significance [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2011, 49(8): 108-112.
[15] L V Yi-jing, REN Min, WANG Bo, GE Ru-qing, ZHANG Ji-dong. Expressions of EZH2 and CTGF Gene in lung adenocarcinoma [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2011, 49(5): 94-97.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd