|
|
MYEOV与TMB：评价肺癌预后及ICIs疗效的新指标
|
Abstract:
肺癌是目前全球发病率和死亡率最高的恶性肿瘤，精准治疗面临驱动基因突变靶向药物覆盖率不足及免疫检查点抑制剂(ICIs)有效率低的挑战。肿瘤突变负荷(TMB)能够反映新抗原生成潜力，进而影响免疫系统识别并激活抗肿瘤反应的能力，可以作为ICIs治疗疗效的预测标志物，但其具体机制尚不明确。本研究通过整合TCGA、CCLE及cBioPortal数据库的肺癌样本数据，以TMB中位值分组鉴定出751个上调差异表达基因(DEGs)，与1170个预后相关基因取交集获得24个关键基因。多因素Cox分析确定MYEOV为独立预后危险因素(HR > 1)，其在肺癌组织表达显著高于正常组织(p < 0.05)，且高TMB组表达水平更高(p < 0.05)。富集分析显示DEGs主要参与嗅觉传导、脂肪代谢及G蛋白偶联受体信号通路。免疫相关性分析表明MYEOV与TNFSF15、CD80等免疫检查点显著相关(p < 0.05)，且与TMB呈正相关(r = 0.16, p < 0.001)。全外显子测序验证显示肺癌患者TMB水平与体细胞变异数正相关，转录组测序证实MYEOV在癌组织过表达(p < 0.05)。研究结果表明，MYEOV是肺癌独立预后风险基因，其高表达与TMB正相关，且通过调控免疫检查点影响肿瘤微环境，参与免疫逃逸。联合TMB与MYEOV检测有望提升ICIs治疗疗效预测精度，为肺癌精准治疗提供新策略。
Lung cancer currently has the highest global incidence and mortality rates among malignant tumors, with precision treatment facing challenges including insufficient coverage of targeted therapies for driver gene mutations and low response rates to immune checkpoint inhibitors (ICIs). Tumor mutational burden (TMB) reflects neoantigen generation potential and influences immune system recognition and activation of anti-tumor responses, serving as a predictive biomarker for ICIs efficacy. However, its underlying mechanisms remain unclear. This study integrated lung cancer sample data from TCGA, CCLE, and cBioPortal databases, identifying 751 upregulated differentially expressed genes (DEGs) through TMB median-based stratification. Intersection with 1170 prognosis-associated genes yielded 24 key genes. Multivariate Cox analysis identified MYEOV as an independent prognostic risk factor (HR > 1), showing significantly higher expression in tumor tissues versus normal tissues (p < 0.05) and elevated levels in high-TMB groups (p < 0.05). Enrichment analysis revealed DEGs primarily involved in olfactory transduction, lipid metabolism, and G protein-coupled receptor signaling pathways. Immune correlation analysis demonstrated MYEOV’s significant associations with immune checkpoints including TNFSF15 and CD80 (p < 0.05), and positive correlation with TMB (r = 0.16, p < 0.001). Whole exome sequencing (WES) confirmed TMB’s positive correlation with somatic mutation counts, while transcriptome sequencing validated MYEOV overexpression in tumor tissues (p < 0.05). These findings establish MYEOV as an independent prognostic risk gene in lung cancer, with its high expression correlating positively with TMB. MYEOV likely modulates immune checkpoints to influence
| [1] | Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I., et al. (2024) Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 74, 229-263. https://doi.org/10.3322/caac.21834 |
| [2] | (2024) [Chinese Medical Association Guideline for Clinical Diagnosis and Treatment of Lung Cancer (2024 Edition)]. Chinese Journal of Preventive Medicine, 104, 3175-3213. |
| [3] | Allemani, C., Matsuda, T., Di Carlo, V., Harewood, R., Matz, M., Nikšić, M., et al. (2018) Global Surveillance of Trends in Cancer Survival 2000-14 (CONCORD-3): Analysis of Individual Records for 37 513 025 Patients Diagnosed with One of 18 Cancers from 322 Population-Based Registries in 71 Countries. The Lancet, 391, 1023-1075. https://doi.org/10.1016/s0140-6736(17)33326-3 |
| [4] | Cai, L., et al. (2024) [Interpretation of Global Lung Cancer Statistics]. Chinese Journal of Epidemiology, 45, 585-590. |
| [5] | Ruiz-Cordero, R. and Devine, W.P. (2020) Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer. Surgical Pathology Clinics, 13, 17-33. https://doi.org/10.1016/j.path.2019.11.002 |
| [6] | Lahiri, A., Maji, A., Potdar, P.D., Singh, N., Parikh, P., Bisht, B., et al. (2023) Lung Cancer Immunotherapy: Progress, Pitfalls, and Promises. Molecular Cancer, 22, Article No. 40. https://doi.org/10.1186/s12943-023-01740-y |
| [7] | Holder, A.M., Dedeilia, A., Sierra-Davidson, K., Cohen, S., Liu, D., Parikh, A., et al. (2024) Defining Clinically Useful Biomarkers of Immune Checkpoint Inhibitors in Solid Tumours. Nature Reviews Cancer, 24, 498-512. https://doi.org/10.1038/s41568-024-00705-7 |
| [8] | Anagnostou, V., Bardelli, A., Chan, T.A. and Turajlic, S. (2022) The Status of Tumor Mutational Burden and Immunotherapy. Nature Cancer, 3, 652-656. https://doi.org/10.1038/s43018-022-00382-1 |
| [9] | Luchini, C., Bibeau, F., Ligtenberg, M.J.L., Singh, N., Nottegar, A., Bosse, T., et al. (2019) ESMO Recommendations on Microsatellite Instability Testing for Immunotherapy in Cancer, and Its Relationship with PD-1/PD-L1 Expression and Tumour Mutational Burden: A Systematic Review-Based Approach. Annals of Oncology, 30, 1232-1243. https://doi.org/10.1093/annonc/mdz116 |
| [10] | 中国抗癌协会肿瘤标志专业委员会遗传性肿瘤标志物协作组, 中国抗癌协会肿瘤病理专业委员会分子病理协作组. 肿瘤突变负荷检测及临床应用中国专家共识(2020年版) [J]. 中国癌症防治杂志, 2020, 12(5): 485-494. |
| [11] | Sung, W.W.Y., Chow, J.C.H. and Cho, W.C.S. (2020) Tumor Mutational Burden as a Tissue-Agnostic Biomarker for Cancer Immunotherapy. Expert Review of Clinical Pharmacology, 14, 141-143. https://doi.org/10.1080/17512433.2021.1865797 |
| [12] | Adams, S.J., Stone, E., Baldwin, D.R., Vliegenthart, R., Lee, P. and Fintelmann, F.J. (2023) Lung Cancer Screening. The Lancet, 401, 390-408. https://doi.org/10.1016/s0140-6736(22)01694-4 |
| [13] | Wu, J., et al. (2019) [Study of Clinical Outcome and Prognosis in Pediatric Core Binding Factor-Acute Myeloid Leukemia]. Chinese Journal of Hematology, 40, 52-57. |
| [14] | Mezquita, L., Auclin, E., Ferrara, R., Charrier, M., Remon, J., Planchard, D., et al. (2018) Association of the Lung Immune Prognostic Index with Immune Checkpoint Inhibitor Outcomes in Patients with Advanced Non-Small Cell Lung Cancer. JAMA Oncology, 4, 351-357. https://doi.org/10.1001/jamaoncol.2017.4771 |
| [15] | Yuan, M., Huang, L., Chen, J., Wu, J. and Xu, Q. (2019) The Emerging Treatment Landscape of Targeted Therapy in Non-Small-Cell Lung Cancer. Signal Transduction and Targeted Therapy, 4, Article No. 61. https://doi.org/10.1038/s41392-019-0099-9 |
| [16] | Ricciuti, B., Wang, X., Alessi, J.V., Rizvi, H., Mahadevan, N.R., Li, Y.Y., et al. (2022) Association of High Tumor Mutation Burden in Non-Small Cell Lung Cancers with Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade across PD-L1 Expression Levels. JAMA Oncology, 8, 1160-1168. https://doi.org/10.1001/jamaoncol.2022.1981 |
| [17] | Zhang, C., Shen, L., Qi, F., Wang, J. and Luo, J. (2019) Multi‐Omics Analysis of Tumor Mutation Burden Combined with Immune Infiltrates in Bladder Urothelial Carcinoma. Journal of Cellular Physiology, 235, 3849-3863. https://doi.org/10.1002/jcp.29279 |
| [18] | 中国临床肿瘤学会血管靶向治疗专家委员会, 中国临床肿瘤学会非小细胞肺癌专家委员会. 肿瘤突变负荷应用于肺癌免疫治疗的专家共识[J]. 中国肺癌杂志, 2021, 24(11): 743-752. |
| [19] | 唐昊. 非小细胞肺癌免疫治疗疗效的预测生物标志物研究进展[J]. 中国肺癌杂志, 2024, 27(6): 459-465. |
| [20] | Büttner, R., Longshore, J.W., López-Ríos, F., Merkelbach-Bruse, S., Normanno, N., Rouleau, E., et al. (2019) Implementing TMB Measurement in Clinical Practice: Considerations on Assay Requirements. ESMO Open, 4, e000442. https://doi.org/10.1136/esmoopen-2018-000442 |
| [21] | Hellmann, M.D., Ciuleanu, T., Pluzanski, A., Lee, J.S., Otterson, G.A., Audigier-Valette, C., et al. (2018) Nivolumab Plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. New England Journal of Medicine, 378, 2093-2104. https://doi.org/10.1056/nejmoa1801946 |
| [22] | Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I. and Tokino, T. (2023) MYEOV Overexpression Induced by Demethylation of Its Promoter Contributes to Pancreatic Cancer Progression via Activation of the Folate Cycle/c-Myc/mTORC1 Pathway. BMC Cancer, 23, Article No. 85. https://doi.org/10.1186/s12885-022-10433-6 |
| [23] | 曹丽君. 骨髓瘤过表达基因(MYEOV)和ARHGAP1在胰腺癌细胞中的生物学功能及机制研究[D]: [硕士学位论文]. 淮南: 安徽理工大学, 2023. |
| [24] | Zhang, R. and Ma, A. (2021) High Expression of MYEOV Reflects Poor Prognosis in Non-Small Cell Lung Cancer. Gene, 770, Article ID: 145337. https://doi.org/10.1016/j.gene.2020.145337 |
| [25] | Ke, H., Wang, X., Zhou, Z., Ai, W., Wu, Z. and Zhang, Y. (2021) Effect of Weimaining on Apoptosis and Caspase-3 Expression in a Breast Cancer Mouse Model. Journal of Ethnopharmacology, 264, Article ID: 113363. https://doi.org/10.1016/j.jep.2020.113363 |
| [26] | Gulley, J.L., Schlom, J., Barcellos‐Hoff, M.H., Wang, X., Seoane, J., Audhuy, F., et al. (2022) Dual Inhibition of TGF‐β and PD‐L1: A Novel Approach to Cancer Treatment. Molecular Oncology, 16, 2117-2134. https://doi.org/10.1002/1878-0261.13146 |
