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Linking periodontitis with 20 cancers, emphasis on oropharyngeal cancer: a Mendelian randomization analysis – Scientific Reports

Instrument selection

In our study involving 64 exposure factors related to periodontal disease, we meticulously selected an array of high-quality SNP clusters as instrumental variables. The specific number of SNPs varies across different groups, with a maximum of 127 and a minimum of 7. A detailed list of SNPs and associated data can be found in Supplement S2. During the selection of these instrumental variables, we adhered to strict criteria, ensuring that each chosen genetic variable had a profound association with the exposure factors of the study, maintained their independence, and we made every effort to eradicate SNPs that could trigger intermediary effects. We meticulously handled each step to prevent potential weak instrument bias, ensuring the accuracy and reliability of our study results. In certain phases of the analysis, we also adopted suitable strategies, such as reducing the number of SNPs when necessary, to mitigate potential overlaps. The implementation of these stepping stones and strategies was designed to satisfy necessary assumptions and align with our primary screening benchmarks. In Supplement S2, we have provided a detailed display of all the screening procedures and outcomes, offering a comprehensive and profound understanding.

Causal influence of periodontitis on 20 common cancers

MR estimates for different methods, sensitivity and heterogeneity estimates, and visual charts are summarized in Supplement S3. We specially discuss the IVW method here. Figure 2 is an essential demonstration of the IVW results. An increased risk of periodontitis may promote an increased risk of head and neck cancer (p = 0.041, OR 0.999, 95% CI 0.999–1.000). MR-Egger, weighted median, and weighted mode methods showed consistent impact tendencies. Heterogeneity and multi-directionality checks did not show decisive opposition. The remaining 19 cancers (basal cell carcinoma, bladder cancer, brain cancer, breast cancer, cancer of urinary tract, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, liver & bile duct cancer, lung cancer, malignant non-melanoma skin cancer, melanoma skin cancer, oesophageal cancer, ovarian cancer, gastric cancer, liver & bile duct cancer, lung cancer, malignant non-melanoma skin cancer, melanoma skin cancer, oesophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, small intestine cancer, squamous cell carcinoma) did not show statistically significant impacts.

Figure 2
figure 2

Estimated effects of periodontitis on 20 common cancers.

Causal influence of periodontitis on four subtypes of head and neck cancer

Furthermore, head and neck cancer refers to a series of cancers that occur in the anatomical regions of the head and neck. We painstakingly teased apart its four main subtypes, namely laryngeal cancer, malignant neoplasm of thyroid gland, oral cavity cancer and oropharyngeal cancer. Supplement S4 shows detailed results, while Fig. 3 is our major focus for IVW results. The risk of periodontitis may potentially drive an increased risk of oropharyngeal cancer (p = 0.022, OR 0.999, 95% CI 0.999–1.000), with other results in agreement. Heterogeneity and sensitivity tests found no decisive anomalies. The other three subtypes of head and neck cancer did not show positive responses.

Figure 3
figure 3

Estimated effects of periodontitis on 4 subclasses of head and neck cancer.

Impact of three possible mediators

The occurrence, progression, and manifestation of periodontitis mainly operate through changes in the features of oral microorganisms, inflammation factors, and immune cells. Therefore, the function of periodontitis in promoting the risk of oropharyngeal cancer may be mediated by these three factors.

The occurrence of periodontitis can lead to changes in the community of oral microbes, most notably an increase in 19 types of oral microbes and a decrease in 21 types of oral microbes24. Restricted by the current oral microbial GWAS data, we only analyzed the possible mediating roles of 20 oral microbes, including eight relative increases (Alloprevotella tannerae, Filifactor alocis, Fusobacterium nucleatum, Parvimonas, Porphyromonas gingivalis, Prevotella intermedia, Prevotella intermedia Tannerella and Treponema denticola) and 12 relative decreases (Actinomyces oris, Capnocytophaga granulosa, Capnocytophaga leadbetteri, Capnocytophaga sputigena. Corynebacterium durum, Gemella haemolysans, Haemophilus parainfluenzae, Kingella, Neisseria flava, Rothia aeria, Streptococcus sanguinis and Veillonella parvula). The evidence for changes in 20 oral microbes due to the presence of periodontitis is positive, so our mediator analysis only discusses whether these 20 microbes would increase the risk of oropharyngeal cancer. The MR assessment and chat for all the methods are in Supplement S5, while Fig. 4 exhibits the main results. The presence of Fusobacterium nucleatum could possibly lead to an increased risk of oropharyngeal cancer (p = 0.021, OR 0.999, 95% CI 0.998–1.000), with other results and quality assessments in agreement. The occurrence of periodontitis can lead to an increased dominance of F. nucleatum, matching the change in direction of this bacterium’s dominant promotion of oropharyngeal cancer. Thus, F. nucleatum could be an intermediate factor mediating the functionality of periodontitis in promoting oropharyngeal cancer. None of the other 19 microbes had any significant results.

Figure 4
figure 4

Estimated effects of 20 oral microorganisms on oropharyngeal cancer.

The occurrence of periodontitis can lead to concurrent changes in 15 inflammation factors25. Combinining this with the currently available GWAS research data, we explored the possible impacts of 14 of these, including 13 increases (IL-1a, IL-1ß, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IFN-γ, MCP-1, MIP1a, RANTES, and TNF-a) and one decrease (IL-4). The complete results are in Supplement S6, while Fig. 5 exhibits the IVW results. For all the 14 inflammation factors, there was no significant impact seen on oropharyngeal cancer.

Figure 5
figure 5

Estimated effects of 14 inflammatory factors on oropharyngeal cancer.

The presence of periodontitis can trigger the response of 22 different types and states of immune cells26. In our research, we discussed the effects of nine immune cells, including four increases (B cell naïve, CD4+ T cell activated, neutrophil cell, and plasma cell) and five decreases (B cell, B cell memory, CD4+ T cell resting, CD8+ T cell, and T cell). The complete results are in Supplement S7, while Fig. 6 exhibits the IVW results. For the nine immune cells, none had any meaningful effects on oropharyngeal cancer.

Figure 6
figure 6

Estimated effects of 9 immune cells on oropharyngeal cancer.

Causal influence of 20 common cancers on periodontitis

The reverse MR analysis is also an integral part of the study. We used 20 common cancers as exposures and matched them with periodontitis for analysis. The detailed results are shown in Supplement S8, while Fig. 7 presents the IVW results. It was found that the occurrence of basal cell carcinoma (p = 0.020, OR 0.987, 95% CI 0.976–0.998) and endometrial cancer (p = 0.027, OR 0.984, 95% CI 0.970–0.998) might increase the risk of periodontitis. There were no objections from other methods’ verification and heterogeneity judgment. The other 18 common cancers did not affect the risk of periodontitis.

Figure 7
figure 7

Estimated effects of 20 Common cancers on periodontitis.