Objective  To investigate the potential associations between lncRNAs and the risk of oral squamous cell carcinoma (OSCC) and oral precancerous lesions (oral leukoplakia and oral lichen planus) using a two-sample Mendelian randomization (MR) approach.

Methods  Expression profiles were analyzed from the Gene Expression Omnibus database (GSE23558 and GSE85195) to identify differentially expressed lncRNAs. Using the eQTLGen Consortium's cis-eQTLs dataset and genome-wide association analysis data for OSCC and oral precancerous lesions, five two-sample MR models, including inverse variance weighting and MR-Egger regression, were used to assess the causal effects of lncRNAs on OSCC and oral precancerous lesions, using single-nucleotide polymorphisms as instrumental variables. Heterogeneity tests, pleiotropy tests, and sensitivity analyses were performed to assess the reliability and stability of the results. False discovery rate (FDR) and Bonferroni correction were applied to adjust the results.

Results  MR analysis indicated that HCG22 [OR=0.999, 95%CI (0.999, 1.000)] may reduce the risk of OSCC, FAM30A [OR=1.001, 95%CI (1.000, 1.002)] may increase the risk of OSCC, and FAM182B [OR=0.738, 95%CI (0.581, 0.937)] may reduce the risk of oral leukoplakia. However, FDR and Bonferroni analysis confirmed that these results may be false positives. Sensitivity analysis revealed no significant heterogeneity or pleiotropy bias, suggesting that the results are robust.

Conclusion  Current genetic evidence does not support a robust causal relationship between the selected lncRNAs and OSCC or its precancerous lesions. This study provides preliminary genetic insights into the role of lncRNAs in the development of oral precancerous lesions. However, future studies with larger sample sizes, functional validation, and multi-omics integration are needed to further explore their biological mechanisms and clinical potential.

1.Peres MA, Macpherson LMD, Weyant RJ, et al. Oral diseases: a global public health challenge [J]. Lancet, 2019, 394(10194): 249-260. DOI: 10.1016/s0140-6736(19)31146-8.

2.Yasothkumar D, Ramani P, Ramasubramanian A. Clinico-pathological assessment and malignant transformation in patients with oral epithelial dysplasia - a follow-up cohort study[J]. Head Neck Pathol, 2025, 19(1): 96. DOI: 10.1007/s12105-025-01833-8.

3.Kojima S, Kuribayashi N, Goda H, et al. Oral cancer driver gene mutations in oral potentially malignant disorders: clinical significance and diagnostic implications[J]. Discov Oncol, 2025, 16(1): 174. DOI: 10.1007/s12672-025-01923-7.

4.Mattick JS, Amaral PP, Carninci P, et al. Long non-coding RNAs: definitions, functions, challenges and recommendations[J]. Nat Rev Mol Cell Biol, 2023, 24(6): 430-447. DOI: 10.1038/s41580-022-00566-8.

5.Coan M, Haefliger S, Ounzain S, et al. Targeting and engineering long non-coding RNAs for cancer therapy[J]. Nat Rev Genet, 2024, 25(8): 578-595. DOI: 10.1038/s41576-024-00693-2.

6.Tang J, Fang X, Chen J, et al. Long non-coding RNA (lncRNA) in oral squamous cell carcinoma: biological function and clinical application[J]. Cancers (Basel), 2021, 13(23): 5944. DOI: 10.3390/cancers13235944.

7.Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians[J]. BMJ, 2018, 362: k601. DOI: 10.1136/bmj.k601.

8.Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology[J]. Stat Med, 2008, 27(8): 1133-1163. DOI: 10.1002/sim.3034.

9.Li XF, Cai JW, Hu YY, et al. Causal relationship between autoimmune arthritis and temporomandibular disorders[J]. Int Dent J, 2025, 75(2): 596-604. DOI: 10.1016/j.identj.2024.08.006.

10.Lin SH, Brown DW, Machiela MJ. LDtrait: an online tool for identifying published phenotype associations in linkage disequilibrium[J]. Cancer Res, 2020, 80(16): 3443-3446. DOI: 10.1158/0008-5472.Can-20-0985.

11.高永强, 施鹏伟, 师文楷, 等. 长链非编码RNA HCG22在口腔鳞状细胞癌中的表达及作用机制研究[J]. 华西口腔医学杂志, 2021, 39(6): 658-666. [Gao YQ, Shi PW, Shi  WK, et al. Expression and mechanism of long non-coding RNA HCG22 in oral squamous cell carcinoma[J]. West China Journal of Stomatology, 2021, 39(6): 658-666.] DOI: 10.7518/hxkq.2021.06.006.

12.Guo YZ, Sun HH, Wang XT, et al. Transcriptomic analysis reveals key lncRNAs associated with ribosomal biogenesis and epidermis differentiation in head and neck squamous cell carcinoma[J]. J Zhejiang Univ Sci B, 2018, 19(9): 674-688. DOI: 10.1631/jzus.B1700319.

13.尹江, 唐平, 张慧, 等. HCG22靶向miR-17-3p对口腔鳞癌细胞生物学行为的影响[J]. 临床肿瘤学杂志, 2023, 28(8): 693-699. [Yin J, Tang P, Zhang H, et al. Effects of HCG22 on biological behavior of oral squamous cell carcinoma cells by targeting miR-17-3p[J]. Chinese Clinical Oncology, 2023, 28(8): 693-699.] DOI: 10.3969/j.issn.1009-0460.2023.08.004.

14.Fu Y, Liu Y, Nasiroula A, et al. Long non-coding RNA HCG22 inhibits the proliferation, invasion and migration of oral squamous cell carcinoma cells by downregulating miR-425-5p expression[J]. Exp Ther Med, 2022, 23(3): 246. DOI: 10.3892/etm.2022.11171.

15.Wang M, Feng Z, Li X, et al. Assessment of multiple pathways involved in the inhibitory effect of HCG22 on oral squamous cell carcinoma progression[J]. Mol Cell Biochem, 2021, 476(6): 2561-2571. DOI: 10.1007/s11010-021-04091-8.

16.Yin JH, Zeng XL, Ai ZX, et al. Construction and analysis of a lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in oral cancer[J]. BMC Med Genomics, 2020, 13(1): 84. DOI: 10.1186/s12920-020-00741-w.

17.Huang GZ, Wu QQ, Zheng ZN, et al. Identification of candidate biomarkers and analysis of prognostic values in oral squamous cell carcinoma[J]. Front Oncol, 2019, 9: 1054. DOI: 10.3389/fonc.2019.01054.

18.Liu J, Han SY, Cui YB, et al. LncRNA FAM30A suppresses proliferation and metastasis of colorectal carcinoma by blocking the JAK-STAT signalling[J]. J Cell Mol Med, 2025, 29(4): e70421. DOI: 10.1111/jcmm.70421.

19.Ye G, Chen Y. LncRNA FAM30A predicts adverse prognosis and regulates cellular processes in colorectal cancer via modulating miR-21-3p[J]. Turk J Gastroenterol, 2024, 35(7): 532-538. DOI: 10.5152/tjg.2024.23465.

20.Liu J, Li W, Zhang J, et al. Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma[J]. Peer J, 2019, 7: e8021. DOI: 10.7717/peerj.8021.