Int J Stomatol

Int J Stomatol ›› 2026, Vol. 53 ›› Issue (1): 67-75.doi: 10.7518/gjkq.2026208

• Original Articles • Previous Articles     Next Articles

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 E-mail:845884912@qq.com;47300561@hebmu.edu.cn
  • Supported by:
    Central Government Guides Local Science And Technology Development Fund Projects(246Z7762G)

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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

CLC Number: 

  • R739.8

TrendMD: 

Tab 1

GWAS data information"

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

Fig 1

Flow chart for screening SNP"

Tab 2

The outcomes of IVW by forward MR analysis between PD-L1 and head and neck cancer"

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

Tab 3

The outcomes of IVW by reverse MR analysis between PD-L1 and head and neck cancer"

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

Tab 4

The results of MR analysis for PD-L1 on HNSCC"

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

Tab 5

The results of MR analysis for PD-L1 on OC&PC"

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

Tab 6

Sensitivity analysis between PD-L1 and HNSCC， OC&PC"

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

Fig 2

Funnel plot for PD-L1 with the potential relationship with HNSCC"

Fig 3

Funnel plot for PD-L1 with the potential relationship with OC&PC"

Fig 4

MR leave-one-out sensivity analysis between PD-L1 and HNSCC"

Fig 5

MR leave-one-out sensivity analysis between PD-L1 and OC&PC"

Tab 7

IVW evaluates the effect of recognized risk factors on PD-L1"

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.
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