基于DNA损伤修复基因的膀胱癌预后风险模型构建及其在免疫治疗效果预测中的应用

doi:10.3969/j.issn.1009-976X.2024.01.004

摘要/Abstract

摘要： 目的本研究旨在探索构建一个基于DNA损伤修复相关基因（DDRGs）的预测膀胱癌患者生存预后及免疫治疗效果的风险模型。方法首先,从TCGA-BLCA数据集下载的RNA序列及临床信息,通过单变量Cox、最小绝对收缩与选择算法（LASSO）及多变量Cox分析,筛选出与DNA损伤修复相关的基因（DDRGs）,构建预后风险模型;利用Kaplan-Meier生存曲线评估生存差异,通过接收者操作特征（ROC）曲线验证模型性能,并结合临床特征构建列线图进行验证。最后,对临床特征进行了分层分析,并进一步通过基因集富集分析（GSEA）、评估免疫状态和免疫检查点抑制剂（ICIs）的治疗效果。结果通过构建11个DNA损伤修复相关基因的风险模型,显示高风险得分的膀胱癌患者生存率明显低于低风险得分患者。免疫状态的分析揭示了高风险与低风险组之间存在显著差异,且低风险组患者对免疫检查点抑制剂的治疗效果更佳。结论基于DNA损伤修复构建的预后风险模型能有效预测膀胱癌患者的生存预后及其对免疫检查点抑制剂治疗的响应性。

关键词: 膀胱癌, DNA损伤修复, 预后模型, 免疫治疗

Abstract: Objective This study aims to explore the construction of a risk model based on DNA Damage Repair Genes （DDRGs） that can accurately predict the survival prognosis and immunotherapy outcomes of bladder cancer patients. Methods Initially, RNA sequences and clinical information downloaded from the TCGA-BLCA dataset were analyzed through univariate Cox, Least Absolute Shrinkage and Selection Operator （LASSO）, and multivariate Cox analyses to identify DNA Damage Repair Genes （DDRGs） and construct a prognostic risk model. Subsequently, the Kaplan-Meier survival curve was utilized to assess survival differences, the Receiver Operating Characteristic （ROC） curve to validate model performance, and nomograms were constructed incorporating clinical features for further validation.Lastly, clinical features were subjected to stratified analysis, and the treatment effects of immune status and Immune Checkpoint Inhibitors （ICIs） were further evaluated through Gene Set Enrichment Analysis （GSEA）. Results The risk model constructed with 11 DNA damage repair-related genes showed that bladder cancer patients with high-risk scores had significantly lower survival rates than those with low-risk scores. Conclusion The prognostic risk model constructed based on DNA damage repair in this study can effectively predict the survival prognosis of bladder cancer patients and their responsiveness to treatment with Immune Checkpoint Inhibitors （ICIs）.

Key words: bladder cancer, DNA damage repair, prognostic model, immunotherapy

中图分类号:

R737.14

罗鸿程, 张嘉豪, 何朝辉. 基于DNA损伤修复基因的膀胱癌预后风险模型构建及其在免疫治疗效果预测中的应用[J]. 岭南现代临床外科, 2024, 24(01): 26-36.

LUO Hong-cheng, ZHANG Jia-hao, HE Zhao-hui. Construction of a bladder cancer prognostic risk model based on DNA damage repair and its application in predicting the effectiveness of immunotherapy[J]. Lingnan Modern Clinics In Surgery, 2024, 24(01): 26-36.

参考文献

[1] Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] Dyrskjøt L, Hansel DE, Efstathiou JA, et al.Bladder cancer[J]. Nat Rev Dis Primers, 2023, 9(1): 58.
[3] Lopez-Beltran A, Cookson MS, Guercio BJ, et al.Advances in diagnosis and treatment of bladder cancer[J]. BMJ, 2024: e076743.
[4] Xie D, Jiang B, Wang S, et al.The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer[J]. Front Cell Dev Biol, 2023, 11: 1200466.
[5] Roos WP, Thomas AD, Kaina B.DNA damage and the balance between survival and death in cancer biology[J]. Nat Rev Cancer, 2016, 16(1): 20-33.
[6] Tiwari V, Wilson DM.DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging[J]. Am J Hum Genet, 2019, 105(2): 237-257.
[7] Carusillo A, Mussolino C.DNA Damage: From Threat to Treatment[J]. Cells, 2020, 9(7):1665.
[8] Huang AC, Cheng YD, Huang LH, et al.Casticin Induces DNA Damage and Impairs DNA Repair in Human Bladder Cancer TSGH-8301 Cells[J]. Anticancer Res, 2019, 39(4): 1839-1847.
[9] Chien TM, Wu KH, Chuang YT, et al.Withaferin a Triggers Apoptosis and DNA Damage in Bladder Cancer J82 Cells through Oxidative Stress[J]. Antioxidants, 2021, 10(7): 1063.
[10] Shi ZD, Hao L, Han XX, et al.Targeting HNRNPU to overcome cisplatin resistance in bladder cancer[J]. Mol Cancer, 2022, 21(1): 37.
[11] Teo MY, Bambury RM, Zabor EC, et al.DNA Damage Response and Repair Gene Alterations Are Associated With Improved Survival In Patients With Platinum-Treated Advanced Urothelial Carcinoma[J]. Clin Cancer Res, 2017, 23(14): 3610-3618.
[12] Lopez-Beltran A, Cimadamore A, Blanca A, et al.Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer[J]. Cancers, 2021, 13(1): 131.
[13] Song D, Powles T, Shi L, et al.Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches[J]. J Pathol, 2019, 249(2): 151-165.
[14] Voutsadakis IA.Urothelial Bladder Carcinomas with High Tumor Mutation Burden Have a Better Prognosis and Targetable Molecular Defects beyond Immunotherapies[J]. Curr Oncol, 2022, 29(3): 1390-1407.
[15] Yang Z, Xu Y, Bi Y, et al.Immune escape mechanisms and immunotherapy of urothelial bladder cancer[J]. J Clin Transl Res, 2021, 7(4): 485-500.
[16] Bhattacharjee S, Sullivan MJ, Wynn RR, et al.PARP inhibitors chemopotentiate and synergize with cisplatin to inhibit bladder cancer cell survival and tumor growth[J]. BMC Cancer, 2022, 22(1): 312.
[17] Criscuolo D, Morra F, Giannella R, et al.New combinatorial strategies to improve the PARP inhibitors efficacy in the urothelial bladder Cancer treatment[J]. J Exp Clin Cancer Res, 2019, 38(1): 91.
[18] Shi C, Qin K, Lin A, et al.The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy[J]. J Exp Clin Cancer Res, 2022, 41(1): 268.
[19] Xu Y, Nowsheen S, Deng M.DNA Repair Deficiency Regulates Immunity Response in Cancers: Molecular Mechanism and Approaches for Combining Immunotherapy[J]. Cancers, 2023, 15(5): 1619.
[20] Choi S, Srivas R, Fu KY, et al.Quantitative proteomics reveal ATM kinase-dependent exchange in DNA damage response complexes[J]. J Proteome Res, 2012, 11(10): 4983-4991.
[21] Park JJ, Lim KH, Baek KH.Annexin-1 regulated by HAUSP is essential for UV-induced damage response[J]. Cell Death Dis, 2015, 6(2): e1654.
[22] Teng PC, Huang SP, Liu CH, et al.Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis[J]. Int J Mol Sci, 2021, 22(21): 11771.
[23] Ok CY, Medeiros LJ, Thakral B, et al.High-grade B-cell lymphomas with TdT expression: a diagnostic and classification dilemma[J]. Mod Pathol, 2019, 32(1): 48-58.
[24] Zhou H, Wu L, Yu L, et al.Identify a DNA Damage Repair Gene Signature for Predicting Prognosis and Immunotherapy Response in Cervical Squamous Cell Carcinoma[J]. J Oncol, 2022, 2022: 8736575.
[25] Mahajan K. hPso4/hPrp19: a critical component of DNA repair and DNA damage checkpoint complexes[J]. Oncogene, 2016, 35(18): 2279-2286.
[26] Van Maldegem F, Maslen S, Johnson CM, et al.CTNNBL1 facilitates the association of CWC15 with CDC5L and is required to maintain the abundance of the Prp19 spliceosomal complex[J]. Nucleic Acids Res, 2015, 43(14): 7058-7069.
[27] Balmus G, Lim PX, Oswald A, et al.HUS1 regulates in vivo responses to genotoxic chemotherapies[J]. Oncogene, 2016, 35(5): 662-669.
[28] Vidotto T, Nersesian S, Graham C, et al.DNA damage repair gene mutations and their association with tumor immune regulatory gene expression in muscle invasive bladder cancer subtypes[J]. J Immunother Cancer, 2019, 7(1): 148.
[29] Chatzinikolaou G, Karakasilioti I, Garinis GA.DNA damage and innate immunity: links and trade-offs[J]. Trends Immunol, 2014, 35(9): 429-435.
[30] Grivennikov SI, Greten FR, Karin M.Immunity, inflammation, and cancer[J]. Cell, 2010, 140(6): 883-899.
[31] Cerboni C, Fionda C, Soriani A, et al.The DNA Damage Response: A Common Pathway in the Regulation of NKG2D and DNAM-1 Ligand Expression in Normal, Infected, and Cancer Cells[J]. Front Immunol, 2014, 4: 508.
[32] Tellez CS, Juri DE, Do K, et al.EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells[J]. Cancer Res, 2011, 71(8): 3087-3097.
[33] Dumauthioz N, Labiano S, Romero P.Tumor Resident Memory T Cells: New Players in Immune Surveillance and Therapy[J].Front Immunol, 2018, 9: 2076.
[34] Jin K, Yu Y, Zeng H, et al.CD103+CD8+ tissue-resident memory T cell infiltration predicts clinical outcome and adjuvant therapeutic benefit in muscle-invasive bladder cancer[J].Br J Cancer, 2022, 126(11): 1581-1588.
[35] Scholler N, Perbost R, Locke FL, et al.Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma[J]. Nat Med, 2022, 28(9): 1872-1882.