国际口腔医学杂志

国际口腔医学杂志 ›› 2026, Vol. 53 ›› Issue (1): 67-75.doi: 10.7518/gjkq.2026208

• 论著 • 上一篇    下一篇

程序性细胞死亡配体1与头颈癌风险的孟德尔随机化研究

尚宏悦(),刘铁军(),姚曼曼,路月亭,董博,宋炜晶,张纪傲   

  1. 河北医科大学第四医院口腔科 石家庄 050000
  • 收稿日期:2024-08-06 修回日期:2025-05-31 出版日期:2026-01-01 发布日期:2025-12-31
  • 通讯作者: 刘铁军
  • 作者简介:尚宏悦，住院医师，硕士，Email：845884912@qq.com
  • 基金资助:
    中央引导地方科技发展资金项目(246Z7762G)

A Mendelian randomization study of programmed cell death ligand 1 with the risk of head and neck cancer

Hongyue Shang(),Tiejun Liu(),Manman Yao,Yueting Lu,Bo Dong,Weijing Song,Ji’ao Zhang   

  1. Dept. of Stomatology, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China
  • Received:2024-08-06 Revised:2025-05-31 Online:2026-01-01 Published:2025-12-31
  • Contact: Tiejun Liu
  • Supported by:
    Central Government Guides Local Science And Technology Development Fund Projects(246Z7762G)

RichHTML

2

PDF (PC)

13

摘要：

目的 评估程序性细胞死亡配体1（PD-L1）与不同类型头颈癌风险之间的因果关系。 方法 利用大规模遗传数据进行孟德尔随机化（MR）分析，通过逆方差加权法（IVW）、孟德尔随机化-艾格法（MR-Egger）、简单模式法和加权中位数法等方法评估PD-L1与不同类型头颈癌风险之间的因果关系。同时采用 MR-Egger和孟德尔随机化多效性残差和离群值（MR-PRESSO）来评估水平多效性，Cochran’s Q检验来评估异质性，留一法实验来评估敏感性。 结果 遗传预测结果显示，PD-L1与头颈部鳞状细胞癌（HNSCC）（OR=1.000 3，95%CI：1.000 0~1.000 6，P=0.049）、口腔及口咽癌（OC&PC）（OR=1.000 3，95%CI：1.000 1~1.000 6，P=0.018）存在因果关系。 结论 本研究分析表明，PD-L1是HNSCC、OC&PC的危险因素。

关键词: 孟德尔随机化, 程序性死亡配体1, 头颈癌, 风险

Abstract:

Objective　This study aimed to assess the causal relationship between programmed cell death ligand 1 (PD-L1) and the risk of head and neck cancer. Methods　Mendelian randomization (MR) was performed using large-scale genetic data to evaluate the causal relationship between PD-L1 and the risk of different types of head and neck cancers via inverse variance weighted (IVW), Mendelian randomization-Egger (MR-Egger), simple mode, and weighted median. Additionally, MR-Egger and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were used to analyze horizontal pleiotropy, Cochran’s Q test was performed to examine heterogeneity, and leave-one-out experiment was conducted to measure sensitivity. Results　The genetic prediction results revealed a causal relationship between PD-L1 and head and neck squamous cell carcinoma (HNSCC) (OR=1.000 3, 95%CI: 1.000 0-1.000 6, P=0.049) and between PD-L1 and oral cavity and oropharyngeal cancer (OC&PC) (OR=1.000 3, 95%CI: 1.000 1-1.000 6, P=0.018). Conclusion　PD-L1 may be a risk factor for the development of HNSCC and OC&PC.

Key words: Mendelian randomization, programmed cell death ligand 1, head and neck cancer, risk

中图分类号: 

  • R739.8

表 1

GWAS数据信息"

因素类型GWAS ID公布年份数据来源样本数量/例SNP数量/个人群范围
暴露因素PD-L1prot-a-4312018GWAS-Catlog3 3014 010 534 735欧洲人
结局因素HNSCCieu-b-49122021UK Biobank病例组1 106对照组372 016409 655 080欧洲人
OC&PCieu-b-49622021UK Biobank病例组839对照组372 016409 185 233欧洲人
LCieu-b-49132021UK Biobank病例组273对照组372 0167 239 512欧洲人
OCieu-b-49612021UK Biobank病例组357对照组372 0167 723 107欧洲人
OPCieu-b-49682021UK Biobank病例组494对照组372 0168 283 869欧洲人

图 1

筛选SNP的流程图"

表 2

PD-L1与头颈癌的正向MR分析IVW结果"

SNP相关参数HNSCCOC&PCLCOCOPC
SNP7167434756
效应估计值0.000 30.000 33.31×10-50.000 10.000 1
标准误0.000 10.000 19.26×10-59.84×10-50.000 1
P值0.049 20.017 70.721 10.135 00.259 7

表 3

PD-L1与头颈癌的反向MR分析IVW结果"

SNP相关参数HNSCCOC&PCLCOCOPC
SNP9694536285
效应估计值3.865 21.644 9-8.255 312.307 0-7.652 2
标准误4.698 85.455 814.090 410.100 27.318 9
P值0.410 70.763 00.558 00.223 00.295 8

表 4

PD-L1对HNSCC的MR分析结果"

MR方法效应估计值标准误P值OR95%CI
IVW0.000 30.000 10.049 21.000 31.000 0~1.000 6
MR-Egger0.000 20.000 30.494 61.000 20.999 6~1.000 9
加权模式法0.000 30.000 50.554 21.000 30.999 3~1.001 3
简单模式法0.000 20.000 50.642 41.000 20.999 2~1.001 2
加权中位数法0.000 30.000 20.164 81.000 30.999 9~1.000 7

表 5

PD-L1对OC&PC的MR分析结果"

MR方法

效应估

计值

标准误P值OR95%CI
IVW0.000 30.000 10.017 71.000 31.000 1~1.000 6
MR-Egger0.000 30.000 30.342 61.000 30.999 7~1.001 0
加权模式法2.98×10-50.000 50.948 11.000 00.999 1~1.000 9
简单模式法-4.13×10-50.000 50.930 00.999 90.999 0~1.000 9
加权中位数法0.00020.000 20.216 21.000 20.999 9~1.000 6

表 6

PD-L1与HNSCC、OC&PC间MR的敏感性分析"

结局因素MR方法异质性检验多效性检验
Cochran’s QP值MR-Egger 截距P值
HNSCC

IVW

MR-Egger

68.830.528.43×10-60.88
68.800.48
OC&PCIVW68.430.39-1.67×10-60.98
MR-Egger68.430.36

图2

PD-L1与HNSCC异质性检验的漏斗图横轴表示PD-L1（βIV），纵轴表示效应估计值（1/SEIV）。图中的每个点代表1个SNP，蓝色直线表示估计的因果效应。"

图 3

PD-L1与和OC&PC敏感性分析的漏斗图横轴表示PD-L1（βIV），纵轴表示效应估计值（1/SEIV）。图中的每个点代表1个SNP，蓝色直线表示估计的因果效应。"

图 4

PD-L1与HNSCC的留一法敏感性分析黑点表示PD-L1中每个SNP产生的标准差（SD）增加时，对应的对数优势比（logOR）；黑线水平线段为95%CI范围；红线表示所有SNP组合的因果估计。"

图 5

PD-L1与OC&PC的留一法敏感性分析黑点表示PD-L1中每个 SNP 产生的标准差（SD）增加时，对应的对数优势比（logOR）；黑线水平线段为 95%CI范围；红线表示所有SNP组合的因果估计。"

表 7

IVW评估公认危险因素对PD-L1的影响"

暴露因素结局（PD-L1）
GWAS IDSNP数量/个P值OR（95%CI）
HPVprot-c-2623_54_4220.591.01（0.96~1.07）
终身性伴侣的数量ukb-b-42563470.841.03（0.77~1.37）
吸烟量ieu-b-48773900.701.03（0.90~1.18）
每周酒精摄入量ieu-b-732550.801.04（0.77~1.39）
体重指数ieu-b-408120.821.02（0.88~1.17）
[1] Mody MD, Rocco JW, Yom SS, et al. Head and neck cancer[J]. Lancet, 2021, 398(10318): 2289-2299.
[2] Thakur N, Paik KY, Hwang G, et al. High expression of PD-L1 is associated with better survival in pancreatic/periampullary cancers and correlates with epithelial to mesenchymal transition[J]. Diagnostics (Basel), 2021, 11(4): 597.
[3] Xiao M, Xie L, Cao G, et al. CD4+ T-cell epitope-based heterologous prime-boost vaccination poten-tiates anti-tumor immunity and PD-1/PD-L1 immunotherapy[J]. J Immunother Cancer, 2022, 10(5): e004022.
[4] Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer[J]. Am J Cancer Res, 2020, 10(3): 727-742.
[5] Hassen G, Kasar A, Jain N, et al. Programmed death-ligand 1 (PD-L1) positivity and factors asso-ciated with poor prognosis in patients with gastric cancer: an umbrella meta-analysis[J]. Cureus, 2022, 14(4): e23845.
[6] Munari E, Marconi M, Querzoli G, et al. Impact of PD-L1 and PD-1 expression on the prognostic significance of CD8+ tumor-infiltrating lymphocytes in non-small cell lung cancer[J]. Front Immunol, 2021, 12: 680973.
[7] Peng L, Fang H, Yang X, et al. Analysis of combination therapy of immune checkpoint inhibitors in osteosarcoma[J]. Front Chem, 2022, 10: 847621.
[8] Blažek T, Petráš M, Hurník P, et al. High PD-L1 expression on immune cells along with increased density of tumor-infiltrating lymphocytes predicts a favorable survival outcome for patients with loco-regionally advanced head and neck cancer: early results from a prospective study[J]. Front Oncol, 2024, 14: 1346793.
[9] Schneider S, Kadletz L, Wiebringhaus R, et al. PD-1 and PD-L1 expression in HNSCC primary cancer and related lymph node metastasis-impact on clinical outcome[J]. Histopathology, 2018, 73(4): 573-584.
[10] Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians[J]. BMJ, 2018, 362: k601.
[11] Gormley M, Dudding T, Sanderson E, et al. A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer[J]. Nat Commun, 2020, 11(1): 6071.
[12] Chen G, Xie J, Liang T, et al. Inflammatory Bowel disease promote oral cancer and pharyngeal cancer: new evidence of Mendelian randomization[J]. Acta Otolaryngol, 2022, 142(2): 191-196.
[13] Gui L, He X, Tang L, et al. Obesity and head and neck cancer risk: a Mendelian randomization study[J]. BMC Med Genomics, 2023, 16(1): 200.
[14] Gormley M, Dudding T, Thomas SJ, et al. Evalua-ting the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization[J]. Elife, 2023, 12: e82674.
[15] Chen G, Xie J, Liu D, et al. Causal effects of education attainment on oral and oropharyngeal cancer: new evidence from a meta-analysis and Mendelian randomization study[J]. Front Public Health, 2023, 11: 1132035.
[16] Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J]. Nat Genet, 2018, 50(5): 693-698.
[17] Lin Y, Wang SJ, Fan ZP, et al. A causal analysis of the relationship between exposure to sunlight and colorectal cancer risk: a Mendelian randomization study[J]. Medicine (Baltimore), 2024, 103(18): e37991.
[18] Levin MG, Judy R, Gill D, et al. Genetics of height and risk of atrial fibrillation: a Mendelian rando-mization study[J]. PLoS Med, 2020, 17(10): e100-3288.
[19] Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors[J]. Eur J Epidemiol, 2015, 30(7): 543-552.
[20] Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44(2): 512-525.
[21] Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted Median estimator[J]. Genet Epidemiol, 2016, 40(4): 304-314.
[22] Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption[J]. Int J Epidemiol, 2017, 46(6): 1985-1998.
[23] Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epide-miol, 2013, 37(7): 658-665.
[24] Racovitan V, Goodman E, Cheung WY, et al. Human papillomavirus (HPV) related oropharyngeal cancers in Canada: a multicenter retrospective cohort study[J]. Hum Vaccin Immunother, 2025, 21(1): 2486768.
[25] Sanders AE, Slade GD, Patton LL. National prevalence of oral HPV infection and related risk factors in the U.S. adult population[J]. Oral Dis, 2012, 18(5): 430-441.
[26] Vu H, Shin YJ, Kong MS, et al. Smoking and drin-king adjusted association between head and neck cancers and oral health status related to periodontitis: a meta-analysis[J]. J Korean Med Sci, 2021, 36(15): e98.
[27] Auguste A, Joachim C, Deloumeaux J, et al. Head and neck cancer risk factors in the French West Indies[J]. BMC Cancer, 2021, 21(1): 1071.
[28] Suzuki S, Yamaji T, Iwasaki M, et al. Body mass index, height, and head and neck cancer risk: the Japan public health center-based prospective study[J]. J Epidemiol, 2025, 35(4): 170-177.
[29] Vesely MD, Zhang T, Chen L. Resistance mechanisms to anti-PD cancer immunotherapy[J]. Annu Rev Immunol, 2022, 40: 45-74.
[30] 赵万, 奉林, 许丽华, 等. PD-L1多态性与105例晚期非小细胞肺癌铂类化疗敏感性及预后关系研究[J]. 中华肿瘤防治杂志, 2021, 28(1): 56-61, 72.
Zhao W, Feng L, Xu LH, et al. Relationship between PD-L1 polymorphism and platinum chemosensitivity and prognosis of 105 patients with advanced non-small cell lung cancer[J]. Chin J Cancer Prev Treat, 2021, 28(1): 56-61, 72.
[31] Xin ZD, You LT, Li J, et al. Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade[J]. Int Immunopharmacol, 2023, 121: 110469.
[32] Makrantonakis AE, Zografos E, Gazouli M, et al. PD-L1 gene polymorphisms rs822336 G>C and rs822337 T>A: promising prognostic markers in triple negative breast cancer patients[J]. Medicina (Kaunas), 2022, 58(10): 1399.
[33] Cao W, Zhang X, Li R, et al. Lipid core-shell nanoparticles co-deliver FOLFOX regimen and siPD-L1 for synergistic targeted cancer treatment[J]. J Control Release, 2024, 368: 52-65.
[34] Chen MF, Chen PT, Chen WC, et al. The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression[J]. Oncotarget, 2016, 7(7): 7913-7924.
[35] Zhang X, Yang Y, Zhao H, et al. Correlation of PD-L1 expression with CD8+ T cells and oxidative stress-related molecules NRF2 and NQO1 in eso-phageal squamous cell carcinoma[J]. J Pathol Clin Res, 2024, 10(4): e12390.
[36] Li X, Cong J, Zhou X, et al. JunD-miR494-CUL3 axis promotes radioresistance and metastasis by facilitating EMT and restraining PD-L1 degradation in esophageal squamous cell carcinoma[J]. Cancer Lett, 2024, 587: 216731.
[37] Molina OE, LaRue H, Simonyan D, et al. Regulatory and memory T lymphocytes infiltrating prostate tumors predict long term clinical outcomes[J]. Front Immunol, 2024, 15: 1372837.
[38] Shang A, Wang W, Gu C, et al. Long non-coding RNA HOTTIP enhances IL-6 expression to poten-tiate immune escape of ovarian cancer cells by upre-gulating the expression of PD-L1 in neutrophils[J]. J Exp Clin Cancer Res, 2019, 38(1): 411.
[39] Anastasiadou E, Stroopinsky D, Alimperti S, et al. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas[J]. Leukemia, 2019, 33(1): 132-147.
[40] Caraban BM, Matei E, Cozaru GC, et al. PD-L1, CD4+ , and CD8+ tumor-infiltrating lymphocytes (TILs) expression profiles in melanoma tumor microenvironment cells[J]. J Pers Med, 2023, 13(2): 221.
[41] Lin MS, Monroig-Bosque PC, Coffey DM, et al. Comparative analysis of PD-L1 expression and tumor-infiltrating lymphocytes in metaplastic breast carcinoma and gynecologic carcinosarcoma: a single-institution retrospective study[J]. Ann Diagn Pathol, 2024, 73: 152360.
[42] Nishimura CD, Pulanco MC, Cui W, et al. PD-L1 and B7-1 cis-interaction: new mechanisms in immune checkpoints and immunotherapies[J]. Trends Mol Med, 2021, 27(3): 207-219.
[43] 宋攀, 颜晓晴, 姜燕慧, 等. PD-1/L1抑制剂在头颈部鳞状细胞癌治疗中的应用进展[J]. 临床耳鼻咽喉头颈外科杂志, 2022, 36(4): 315-320.
Song P, Yan XQ, Jiang YH, et al. The research pro-gress of PD-1/L1 inhibitors application in the treatment of head and neck squamous cell carcinoma[J]. J Clin Otorhinolaryngol Head Neck Surg, 2022, 36(4): 315-320.
[1] 李娇娇,刘钧. 外伤牙早期固定正畸治疗的研究进展[J]. 国际口腔医学杂志, 2024, 51(4): 498-504.
[2] 李东娜, 翟浩嫣, 刘春艳. 牙周正畸联合治疗的研究进展[J]. 国际口腔医学杂志, 2024, 51(3): 326-336.
[3] 王钢,陈卓. 邻面去釉后釉质表面患龋风险控制的描述性综述[J]. 国际口腔医学杂志, 2023, 50(4): 395-400.
[4] 孙晓倩, 张军. 机械力环境影响头颈癌生物学行为及作用机制的研究进展[J]. 国际口腔医学杂志, 2023, 50(4): 414-418.
[5] 杨明燕,张帆,赵蕾. 口腔菌群变化影响放射治疗和化学治疗相关性口腔黏膜炎病程的研究进展[J]. 国际口腔医学杂志, 2023, 50(1): 43-51.
[6] 白皓亮,杨禾,赵蕾. 牙周病风险评估及预后判断工具的研究进展[J]. 国际口腔医学杂志, 2021, 48(6): 696-702.
[7] 邢桂琪,郭林溪,苏勤. 根管治疗后疾病的综合评估和治疗决策[J]. 国际口腔医学杂志, 2021, 48(5): 579-584.
[8] 邓晓宇,张蕴涵,邹静. 低龄儿童龋的早期生物学管理[J]. 国际口腔医学杂志, 2020, 47(5): 581-588.
[9] 陈艳艳,彭显,周学东,程磊. 定量光导荧光技术在龋病及牙周疾病诊治中的应用[J]. 国际口腔医学杂志, 2019, 46(6): 699-704.
[10] 王晓波,林世耀,李霞. 母亲与儿童龋病关系的研究进展[J]. 国际口腔医学杂志, 2019, 46(4): 469-474.
[11] 杜琳玲 冯娟. 人中性粒细胞肽-1~3及其与患龋风险的关系[J]. 国际口腔医学杂志, 2015, 42(6): 699-702.
[12] 杨晓喻，刘长虹，刘伟进，周震. 1例前牙即刻种植的过程与思考——基于风险评估的术式选择与修复设计[J]. 国际口腔医学杂志, 2015, 42(2): 130-134.
[13] 曹昊天 吴也可综述 潘剑审校. 长期服用抗凝药物患者拔牙围手术期的处理[J]. 国际口腔医学杂志, 2012, 39(5): 617-619.
[14] 肖逊1综述 罗云2审校. 糖尿病患者口腔颌面外科围手术期的风险和预防[J]. 国际口腔医学杂志, 2011, 38(6): 712-716.
[15] 李婧综述 李江审校. 上皮-钙黏着蛋白及其启动子甲基化在头颈癌中的作用[J]. 国际口腔医学杂志, 2011, 38(2): 171-173.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!