孟德尔随机化在暴露因素与宫颈癌因果关系中的研究进展

doi:10.12280/gjfckx.20241033

摘要/Abstract

摘要：

了解潜在危险因素对于预防宫颈癌的发生至关重要。推断危险因素与疾病之间因果关系常采用随机对照试验与观察性研究，但在实际操作中，均有一定程度的局限性。近年来，孟德尔随机化（Mendelian randomization，MR）在癌症研究中备受关注，为发现危险因素及探究潜在治疗提供了新视角。MR使用遗传变异作为工具变量，模拟分析可调整的危险因素与疾病之间的关系，可以在流行病学研究中探索因果关系。综述MR在宫颈癌中的研究进展，总结多种危险因素与宫颈癌风险之间的内在联系，并阐述MR分析在宫颈癌研究领域中的实践与应用。

关键词: 宫颈肿瘤, 危险因素, 孟德尔随机化分析, 因果律, 工具变量

Abstract:

Understanding the potential risk factors is crucial for preventing the occurrence of cervical cancer. Inferring the causality relationships between risk factors and diseases often uses randomized controlled trials and observational studies, but in practice, there are some limitations in both cases. In recent years, Mendelian randomization (MR) has gained attention in cancer research, offering new perspectives for identifying risk factors and exploring potential treatments. MR uses genetic variants as instrumental variables to simulate analysis the relationship between modifiable risk factors and diseases, enabling causal inference in epidemiological studies. This review summarizes the research progress of MR in cervical cancer, summarizes the intrinsic connections between various risk factors and the risk of cervical cancer, and discusses the practice and application of MR analysis in the field of cervical cancer research.

Key words: Uterine cervical neoplasms, Risk factors, Mendelian randomization analysis, Causality, Instrumental variables

郭竞, 张茂祥, 周春鹤, 刘思宁, 李惠艳. 孟德尔随机化在暴露因素与宫颈癌因果关系中的研究进展[J]. 国际妇产科学杂志, 2025, 52(2): 169-174.

GUO Jing, ZHANG Mao-xiang, ZHOU Chun-he, LIU Si-ning, LI Hui-yan. The Progress of Mendelian Randomization in the Study of the Causal Relationship between Exposure Factors and Cervical Cancer[J]. Journal of International Obstetrics and Gynecology, 2025, 52(2): 169-174.

参考文献 53

[1]	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3):229-263. doi: 10.3322/caac.21834.
[2]	Castle PE, Einstein MH, Sahasrabuddhe VV. Cervical cancer prevention and control in women living with human immunodeficiency virus[J]. CA Cancer J Clin, 2021, 71(6):505-526. doi: 10.3322/caac.21696.
[3]	Caird H, Simkin J, Smith L, et al. The Path to Eliminating Cervical Cancer in Canada: Past, Present and Future Directions[J]. Curr Oncol, 2022, 29(2):1117-1122. doi: 10.3390/curroncol29020095. pmid: 35200594
[4]	Wang X, Ji X. Sample Size Estimation in Clinical Research: From Randomized Controlled Trials to Observational Studies[J]. Chest, 2020, 158(1S):S12-S20. doi: 10.1016/j.chest.2020.03.010. pmid: 32658647
[5]	Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review[J]. Res Synth Methods, 2019, 10(4):486-496. doi: 10.1002/jrsm.1346. pmid: 30861319
[6]	Gala H, Tomlinson I. The use of Mendelian randomisation to identify causal cancer risk factors: promise and limitations[J]. J Pathol, 2020, 250(5):541-554. doi: 10.1002/path.5421.
[7]	Sheehan NA, Didelez V, Burton PR, et al. Mendelian randomisation and causal inference in observational epidemiology[J]. PLoS Med, 2008, 5(8):e177. doi: 10.1371/journal.pmed.0050177.
[8]	Harding JL, Shaw JE, Peeters A, et al. Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation[J]. Diabetes Care, 2015, 38(2):264-270. doi: 10.2337/dc14-1996. pmid: 25488912
[9]	Pan L, Freedman DS, Gillespie C, et al. Incidences of obesity and extreme obesity among US adults: findings from the 2009 Behavioral Risk Factor Surveillance System[J]. Popul Health Metr, 2011, 9(1):56. doi: 10.1186/1478-7954-9-56. pmid: 22004984
[10]	Yuan S, Kar S, Carter P, et al. Is Type 2 Diabetes Causally Associated With Cancer Risk? Evidence From a Two-Sample Mendelian Randomization Study[J]. Diabetes, 2020, 69(7):1588-1596. doi: 10.2337/db20-0084. pmid: 32349989
[11]	Gillani SW, Zaghloul HA, Ansari IA, et al. Multivariate Analysis on the Effects of Diabetes and related Clinical Parameters on Cervical Cancer Survival Probability[J]. Sci Rep, 2019, 9(1):1084. doi: 10.1038/s41598-018-37694-1. pmid: 30705329
[12]	Kim SC, Glynn RJ, Giovannucci E, et al. Risk of high-grade cervical dysplasia and cervical cancer in women with systemic inflammatory diseases: a population-based cohort study[J]. Ann Rheum Dis, 2015, 74(7):1360-1367. doi: 10.1136/annrheumdis-2013-204993. pmid: 24618265
[13]	Wadström H, Frisell T, Sparén P, et al. Do RA or TNF inhibitors increase the risk of cervical neoplasia or of recurrence of previous neoplasia? A nationwide study from Sweden[J]. Ann Rheum Dis, 2016, 75(7):1272-1278. doi: 10.1136/annrheumdis-2015-208263. pmid: 26755797
[14]	Xu M, Chen H, Tan T, et al. Exploring the causal association between rheumatoid arthritis and the risk of cervical cancer: a two-sample Mendelian randomization study[J]. Arthritis Res Ther, 2024, 26(1):35. doi: 10.1186/s13075-023-03240-2. pmid: 38263277
[15]	Gusakov K, Kalinkovich A, Ashkenazi S, et al. Nature of the Association between Rheumatoid Arthritis and Cervical Cancer and Its Potential Therapeutic Implications[J]. Nutrients, 2024, 16(15):2569. doi: 10.3390/nu16152569.
[16]	Drevet G, Duruisseaux M, Maury JM, et al. Lung cancer surgical treatment after solid organ transplantation: A single center 30-year experience[J]. Lung Cancer, 2020, 139:55-59. doi: 10.1016/j.lungcan.2019.10.023. pmid: 31739183
[17]	Zhang M, Wang Y, Wang Y, et al. Association Between Systemic Lupus Erythematosus and Cancer Morbidity and Mortality: Findings From Cohort Studies[J]. Front Oncol, 2022, 12:860794. doi: 10.3389/fonc.2022.860794.
[18]	Foster E, Malloy MJ, Jokubaitis VG, et al. Increased risk of cervical dysplasia in females with autoimmune conditions-Results from an Australia database linkage study[J]. PLoS One, 2020, 15(6):e0234813. doi: 10.1371/journal.pone.0234813.
[19]	Grytten N, Myhr KM, Celius EG, et al. Incidence of cancer in multiple sclerosis before and after the treatment era- a registry- based cohort study[J]. Mult Scler Relat Disord, 2021, 55:103209. doi: 10.1016/j.msard.2021.103209.
[20]	Liu Z, Fan T, Mo X, et al. Association between multiple sclerosis and cancer risk: A two-sample Mendelian randomization study[J]. PLoS One, 2024, 19(3):e0298271. doi: 10.1371/journal.pone.0298271.
[21]	Durrieu G, Dardonville Q, Clanet M, et al. Cervical dysplasia in a patient with multiple sclerosis treated with natalizumab[J]. Fundam Clin Pharmacol, 2019, 33(1):125-126. doi: 10.1111/fcp.12394.
[22]	Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide[J]. J Hepatol, 2006, 45(4):529-538. doi: 10.1016/j.jhep.2006.05.013. pmid: 16879891
[23]	Tian T, Song C, Jiang L, et al. Hepatitis B virus infection and the risk of cancer among the Chinese population[J]. Int J Cancer, 2020, 147(11):3075-3084. doi: 10.1002/ijc.33130.
[24]	Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome[J]. Elife, 2018, 7:e34408. doi: 10.7554/eLife.34408.
[25]	Kim J, Jung JH, Jo H, et al. Risk of uterine cervical cancer in inflammatory bowel disease: a systematic review and meta-analysis[J]. Scand J Gastroenterol, 2023, 58(12):1412-1421. doi: 10.1080/00365521.2023.2238101.
[26]	Yu C, Xu J, Xu S, et al. Exploring genetic associations of Crohn′s disease and ulcerative colitis with extraintestinal cancers in European and East Asian populations[J]. Front Immunol, 2024, 15:1339207. doi: 10.3389/fimmu.2024.1339207.
[27]	Nguyen TB, Do DN, Nguyen-Thi ML, et al. Identification of potential crucial genes and key pathways shared in Inflammatory Bowel Disease and cervical cancer by machine learning and integrated bioinformatics[J]. Comput Biol Med, 2022, 149:105996. doi: 10.1016/j.compbiomed.2022.105996.
[28]	Park S, Lee S, Kim Y, et al. Risk of cancer in pre-dialysis chronic kidney disease: A nationwide population-based study with a matched control group[J]. Kidney Res Clin Pract, 2019, 38(1):60-70. doi: 10.23876/j.krcp.18.0131. pmid: 30866180
[29]	Tang L, Li C, Chen W, et al. Causal Association between Chronic Kidney Disease and Risk of 19 Site-Specific Cancers: A Mendelian Randomization Study[J]. Cancer Epidemiol Biomarkers Prev, 2022, 31(6):1233-1242. doi: 10.1158/1055-9965.EPI-21-1318.
[30]	Franchini M, Lippi G. The intriguing relationship between the ABO blood group, cardiovascular disease, and cancer[J]. BMC Med, 2015, 13:7. doi: 10.1186/s12916-014-0250-y. pmid: 25592962
[31]	Sun T, Mei N, Su Y, et al. Mendelian randomization combined with multi-omics explores the relationship between heart failure and cancer[J]. J Cancer, 2024, 15(10):2928-2939. doi: 10.7150/jca.94142. pmid: 38706896
[32]	Zhang L, Xue B, Yu F, et al. Deciphering the Causal Relationship between Sodium-glucose Cotransporter 2 Inhibition and Cancer Risks: A Comprehensive Mendelian Randomization Study[J]. J Cancer, 2024, 15(12):3903-3912. doi: 10.7150/jca.96435. pmid: 38911377
[33]	Brown E, Heerspink H, Cuthbertson DJ, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications[J]. Lancet, 2021, 398(10296):262-276. doi: 10.1016/S0140-6736(21)00536-5. pmid: 34216571
[34]	Rosoff DB, Bell AS, Jung J, et al. Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function[J]. J Am Coll Cardiol, 2022, 80(7):653-662. doi: 10.1016/j.jacc.2022.05.041. pmid: 35953131
[35]	Revilla G, Cedó L, Tondo M, et al. LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies[J]. Semin Cancer Biol, 2021, 73:134-157. doi: 10.1016/j.semcancer.2020.11.012. pmid: 33249202
[36]	Wang W, Li W, Zhang D, et al. The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting[J]. Genes (Basel), 2024, 15(1):132. doi: 10.3390/genes15010132.
[37]	Huang P, Zhang PF, Li Q. Causal relationship between cannabis use and cancer: a genetically informed perspective[J]. J Cancer Res Clin Oncol, 2023, 149(11):8631-8638. doi: 10.1007/s00432-023-04807-x. pmid: 37099198
[38]	Kang GU, Jung DR, Lee YH, et al. Dynamics of Fecal Microbiota with and without Invasive Cervical Cancer and Its Application in Early Diagnosis[J]. Cancers(Base), 2020, 12(12):3800. doi: 10.3390/cancers12123800.
[39]	Sims TT, Colbert LE, Zheng J, et al. Gut microbial diversity and genus-level differences identified in cervical cancer patients versus healthy controls[J]. Gynecol Oncol, 2019, 155(2):237-244. doi: 10.1016/j.ygyno.2019.09.002. pmid: 31500892
[40]	Kong Y, Liu S, Wang X, et al. Associations between gut microbiota and gynecological cancers: A bi-directional two-sample Mendelian randomization study[J]. Medicine(Baltimore), 2024, 103(13):e37628. doi: 10.1097/MD.0000000000037628.
[41]	Shen X, Wang C, Li M, et al. Identification of CD8+ T cell infiltration-related genes and their prognostic values in cervical cancer[J]. Front Oncol, 2022, 12:1031643. doi: 10.3389/fonc.2022.1031643.
[42]	Li Y, Liu J, Wang Q, et al. The causal effects of genetically determined immune cells on gynecologic malignancies: a Mendelian randomization study[J]. Front Oncol, 2024, 14:1371309. doi: 10.3389/fonc.2024.1371309.
[43]	Pita-Lopez ML, Ortiz-Lazareno PC, Navarro-Meza M, et al. CD28-, CD45RA^null/dim and natural killer-like CD8+ T cells are increased in peripheral blood of women with low-grade cervical lesions[J]. Cancer Cell Int, 2014, 14(1):97. doi: 10.1186/s12935-014-0097-5. pmid: 25278812
[44]	Zhang Z, Wang J, Teng M, et al. The role of serum interleukins in Cancer: A Multi-center Mendelian Randomization study[J]. Int Immunopharmacol, 2024, 137:112520. doi: 10.1016/j.intimp.2024.112520.
[45]	Hye T, Dwivedi P, Li W, et al. Newer insights into the pathobiological and pharmacological basis of the sex disparity in patients with pulmonary arterial hypertension[J]. Am J Physiol Lung Cell Mol Physiol, 2021, 320(6):L1025-L1037. doi: 10.1152/ajplung.00559.2020.
[46]	Li Z, Wang M, Hua M, et al. Association between testosterone and cancers risk in women: a two-sample Mendelian randomization study[J]. Discov Oncol, 2023, 14(1):198. doi: 10.1007/s12672-023-00811-2. pmid: 37924384
[47]	Yu L, Lanqing G, Huang Z, et al. T cell immunotherapy for cervical cancer: challenges and opportunities[J]. Front Immunol, 2023, 14:1105265. doi: 10.3389/fimmu.2023.1105265.
[48]	Louie KS, de Sanjose S, Diaz M, et al. Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries[J]. Br J Cancer, 2009, 100(7):1191-1197. doi: 10.1038/sj.bjc.6604974.
[49]	Nakazawa H, Yamaguchi S, Onuki M, et al. Age at first sexual intercourse among young women with invasive cervical cancer: implications for routine vaccination against human papillomavirus in Japan[J]. Jpn J Clin Oncol, 2023, 53(6):530-533. doi: 10.1093/jjco/hyad017.
[50]	Zhou YY, Chang M, Li CP, et al. Causal effect of age first had sexual intercourse and lifetime number of sexual partners on cervical cancer[J]. Heliyon, 2024, 10(1):e23758. doi: 10.1016/j.heliyon.2023.e23758.
[51]	Sullivan VK, Petersen KS, Kris-Etherton PM. Dried fruit consumption and cardiometabolic health: a randomised crossover trial[J]. Br J Nutr, 2020, 124(9):912-921. doi: 10.1017/S0007114520002007.
[52]	Zuniga KE, Clinton SK, Erdman JW Jr. The interactions of dietary tomato powder and soy germ on prostate carcinogenesis in the TRAMP model[J]. Cancer Prev Res(Phila), 2013, 6(6):548-557. doi: 10.1158/1940-6207.CAPR-12-0443.
[53]	Jin C, Li R, Deng T, et al. Association between dried fruit intake and pan-cancers incidence risk: A two-sample Mendelian randomization study[J]. Front Nutr, 2022, 9:899137. doi: 10.3389/fnut.2022.899137.