In this study, we investigated the causal relationship between five exposure factors (oily fish, celery, pork, average weekly beer and fruit wine consumption, and spirit consumption) and the risk of oral cancer using a GWAS-based MR study. According to the latest public database, the five factor exposures (oily fish, celery, pork, average weekly beer and wine, and sprit consumption) independently have a direct effect on the oral cavity; however, when the intake of these five kinds of foods/drinks occurs simultaneously, pork consumption shows the greatest influence on oral cancer. Thus, our MR study on oral cancer provided a theoretical basis and reference value.
Oral cancer is a public health problem with a high incidence, and despite global evidence-based reports on oral cancer causality,9 public awareness on oral cancer pathogenesis remains low. The International Agency for Research on Cancer has reported through its monograph program that harmful carcinogens, including tobacco (smoked and smokless), alcohol, betel nut chewing, and HPV infection, may increase the risk of oral cancer in humans. The main pathogenic mechanism is that alcohol and tobacco jointly increase mucosal permeability to the carcinogen nitrite.10 Case-control studies have consistently shown that the dietary history of patients with oral cancer is low in fruits and vegetables.11 Large-sample studies have consistently shown that regular consumption of vegetables, citrus fruits, fish, and vegetable oils is the main feature of a low-risk diet for oral cancer, after adjusting for smoking and alcohol intake.12 Patients and medical staff having greater awareness of the risk factors for oral cancer can lead to early diagnosis, which in turn will help improve the survival of oral cancer patients to the greatest extent. Moreover, there is a lack of research on the risk factors for oral cancer in young people.13 At present, the most important step is to check for potential risk factors and possible protective factors, such as diet, to provide a more thorough etiological examination.
The results found the risk of pork consumption to be significantly high for oral cancer even with the influence of alcohol and tobacco. In other words, the effect of pork consumption may be undervalued for the influence of oral cancer. Previous studies have shown that excess energy intake and a low regular consumption of fresh fruits and vegetables are associated with an increased risk for several types of cancer, especially for squamous cell carcinomas in the upper digestive tract. Although the contribution of dietary fat to cancer development has not been fully elucidated, it is generally accepted that this group of nutrients is an important modulator of carcinogenesis.14 The carcinogenic effect of a diet rich in animal fat has also been indicated as possibly related to the ingestion of nitrosamines, which are present in cured meats and products used for food conserving, and heterocyclic amines, which are food-borne carcinogens formed when meat is fried or cooked at high temperatures. Data from a case-control study conducted between 1992 and 1997 in the Canton of Vaud, Switzerland, examining the role of specific food groups and dietary diversity on the risk of oral and pharyngeal cancers, showed that after accounting for education, alcohol, tobacco, and total energy intake, eggs (up to three digits; OR = 2.3), red meat (OR = 2.1), and pork and processed meat (OR = 3.2) had a significantly increased risk of cancer with increased frequency of intake. However, opposite trends were observed for milk (OR = 0.4 for the highest tertile), fish (OR = 0.5), raw vegetables (OR = 0.3), cooked vegetables (OR = 0.1), citrus fruits (OR = 0.4), and other fruits (OR = 0.2).15 Another study investigated the correlation between intestinal cancer and a diet with high meat content and found that a diet with high meat content could induce mutations in the small intestine of mice, leading to intestinal cancer.16 Another study in northern Italy found an association between meat intake and retinol levels, which may reflect the adverse effects of animal fat and cholesterol.17 Therefore, we hypothesized that the mechanism of action of pork on oral cancer might be related to the processing status, the effect of saturated fatty acids and cholesterol, and the proportion of meat in the diet.
Our study has several strengths. First, MR studies can mimic Randomized controlled trials (RCT), which are widely regarded as a method for revealing causality and avoiding reverse causality. At the same time, an MR study is less expensive and labor intensive than an RCT. This is the first MR study to evaluate the association between five exposure factors (oily fish, celery, pork, average weekly beer and fruit wine consumption, and spirit consumption) and oral cancer risk with causality. Second, MR studies can effectively prevent the influence of confounding factors owing to the random assignment of alleles. Third, we rigorously screened for associated SNPS, which are not weak tools in terms of F-statistics.
However, our MR study has some limitations. First, because the GWAS databases in our study were all from European populations and may not be applicable to populations of other ethnic groups, it remains uncertain whether the results can be extrapolated to other populations. Second, we were unable to obtain detailed demographic and clinical data. Therefore, we could not perform further subgroup analyses. Third, our MR study assessed the effects of lifetime exposure, which may have been overestimated in the real world if effective interventions had existed. Finally, epigenetic issues, such as genomic imprinting, maternal effects, and gene silencing, are inevitable weaknesses of MR analysis and may introduce bias.