**5. Risk factors, which potentiate the malignant transformation of the potentially malignant disorders of the oral and maxillofacial region**

Oral cancers are typically preceded by potentially malignant lesions [25, 26], and 50% precursor lesions converted to oral cancers [27]. Oral cancer exhibits significant variations in its incidence and prevalence across different regions worldwide,

*Genetic Revelation of the Potentially Malignant Disorders in the Oral and Maxillofacial… DOI: http://dx.doi.org/10.5772/intechopen.112697*

**Figure 1.** *Risk factors for the malignant transformation of the potentially malignant disorders of the oral and maxillofacial region.*

highlighting its distinct geographic distribution [28]. Oral cancer is a multifactorial lesion influenced by various factors. These risk factors encompass using tobacco, consuming alcohol, prolonged or excessive UV radiation exposure (generally labial carcinoma), viral infection (e.g., Human papillomavirus (HPV)), fungal infection (e.g., Candida), long-term inflammation, weakened immune system, genetic susceptibility, and dietary habits (**Figure 1**) [27].

The primary causes of oral cancer identified by various studies are using tobacco and consuming alcohol [26, 27, 29, 30]. The smoke from cigarettes contains various substances, including nicotine, which affects the central nervous system and the gastrointestinal tract, including the oral cavity [27]. Two nicotine metabolites, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N<sup>0</sup> -nitrosonornicotine (NNN), possess carcinogenic properties [27]. These substances bind to the nicotinic acetylcholine receptor, promoting cell growth and creating a favorable environment for tumor development [27]. Smokeless tobacco (SLT) has also been significantly associated with potentially malignant and malignant oral cavity lesions [31]. The International Agency for Research on Cancer (IARC) monograph confirms a substantial link between SLT use and oral cancer. Marijuana smoke contains cannabinoids, immunosuppressants, and a mixture of potentially mutagenic compounds [32]. A case–control study on head and neck squamous cell carcinoma (HNSCC) found a negative correlation between marijuana use and oral cavity cancers [32]. Ethanol, when metabolized into acetaldehyde, a known carcinogen and tumor promoter, contributes to the development of oral cancer through chronic alcohol consumption [27]. Alcohol often contains carcinogenic impurities, such as polycyclic aromatic

hydrocarbons and nitrosamines [27]. Although alcohol alone does not have a direct association with cancer progression, it synergistically interacts with tobacco to increase the risk of developing cancer [27]. According to the American Cancer Society, heavy smokers and drinkers face a risk of these cancers approximately 30 times higher than that of nonsmokers and nondrinkers. Betel quid chewing has been identified as a risk factor for oral precancerous lesions [33], particularly playing a major role in the development of submucosal fibrosis [30].

The oral microbiota plays a critical role in maintaining human health by contributing to immune response, nutrient digestion, and carcinogen metabolism [27]. It has been observed that patients with oral cancer often have poor oral hygiene [30]. The human oral cavity is colonized by more than 700 different bacterial species, collectively known as the oral microbiome [27]. Certain viruses such as HPV, EBV, Hepatitis B and C, Helicobacter pylori, as well as bacteria, such as *Porphyromonas*, *Fusobacterium nucleatum*, and *Prevotella intermedia,* have been identified as causes of various types of human cancer [27, 30, 34]. Recent studies found that some bacterial activity on oral epithelial cells, especially bacteria from periopathogenic biofilms, for example, *Fusobacterium nucleatum* and *Porphyromonas gingivalis* has the ability to create malignant conditions, which can influence oral oncogenesis [30]. Human papillomavirus (HPV) is a significant risk factor for a specific subset of head and neck squamous cell carcinomas (HNSCC) [27, 35–37]. Among HNSCC cases, HPV16 is the most prevalent type associated with carcinogenesis, followed by HPV18 [27]. HPV16 carries a higher risk for oropharyngeal squamous cell carcinoma (OPSCC). The early proteins of HPV, namely E6 and E7, play a crucial role in HPV-related OPSCC. E6 inhibits the tumor suppressor protein p53, while E7 binds to pRb (retinoblastoma protein) [27].

Oral cancer can develop as a result of chronic irritation in the mucosa [30]. The release of mediators (e.g., cytokines) is triggered by persistent inflammation, which is linked to chronic irritation and subsequently results in DNA damage due to oxidative stress, contributing in the development of cancer [30]. Chronic mucosal trauma is considered both an initiating factor and a progression promoter in oral cancer. It can either cause lesions on healthy mucosa or exacerbate existing lesions [30]. The risk of oral cancer is increased in individuals who undergo transplantation of allogeneic hematopoietic stem cells, particularly those who develop chronic graft-versus-host disease (GvHD) [38]. For the early detection and management of secondary malignant diseases, it is advisable to closely monitor patients who have chronic graftversus-host disease (GvHD) on a regular basis. Bullous forms, plaque-like, ulcerative, erythematous erosions, papular, and white reticular striations are the subtype of oral lichen planus (OLP), a chronic inflammatory disease [39]. Those subtypes can affect any person singularly as well combined. OLP promotes some major cancer hallmarks such as immune evasion and tumor-promoting inflammation, and significantly disturbs the immune system [39].

A genetic predisposition plays a significant role in the development of oral squamous cell carcinoma (OSCC), particularly in tongue and buccal mucosa cancers [27]. However, determining the specific genetic or familial disposition for oral cancer is challenging due to the presence of concurrent risk factors, such as smoking and alcohol use [27]. Aberrant methylation has been observed as an early molecular event in the process of oral carcinogenesis [29]. For instance, gene-specific studies have identified inactivation of the p16INK4a gene through CpG methylation as a crucial event in epithelial dysplasia. Additionally, p16INK4a hypermethylation has been associated with loss of heterozygosity (LOH) [29]. Although genetic loss of

*Genetic Revelation of the Potentially Malignant Disorders in the Oral and Maxillofacial… DOI: http://dx.doi.org/10.5772/intechopen.112697*

heterozygosity is considered a better marker for predicting the risk of malignant progression in potentially malignant oral epithelial lesions (PPOEL), it has not yet been integrated into routine clinical practice [25]. Approximately 86 genes, along with the long interspersed elements 1 (LINE1), have been identified to exhibit hypermethylation associated with oral cancer [29]. Most of these 86 hypermethylated genes have been found to be downregulated and exhibit hypermethylation in their promoter regions in OSCCs compared to normal tissue [29]. Some researchers propose that individuals who inherit an impaired ability to metabolize carcinogens or procarcinogens and repair DNA damage are more susceptible to developing oral malignancies [27].

The risk of developing oral cancer may be increased due to a low fruit and vegetable diet, coupled with a deficiency in vitamin A. Dietary habits have been consistently linked to the development of several types of cancers [40]. Numerous studies seem to indicate that different food compounds could alter or modify cancer cells [40]. In 2019, a systematic study report published by the World Cancer Research Fund (WCRF) suggested that cancer, for example, oral cancer can be reduced by taking vegetables, fruit, whole grains, and legumes rich diet [41]. Submucosal fibrosis, an oral potentially malignant lesion (OPL), was initially considered idiopathic but is now believed to have a multifactorial etiology. Factors, such as capsaicin, present in chilies, as well as deficiencies in iron, zinc, and vitamins, have been implicated [30]. Consuming very hot foods has been identified as a risk factor for potentially malignant disorders, as a study found a significant difference between patients with oral lichen planus (OLP) and a control group [42]. Oxidative stress and antioxidants are important indicators in oral cancer and potentially malignant disorders as they may predict susceptibility to the development of oral cancer. Normal individuals exhibit differences in the levels of both enzymatic and nonenzymatic antioxidants when compared to patients with oral cancer or oral potentially malignant lesions [43]. Additionally, patients with oral potentially malignant lesions or oral cancer show high level of lipid peroxidation and higher oxidative stress than healthy people [43].

Men have a higher tendency to develop oral cancer compared to women. Out of every 100,000 men, approximately 5.8 men are at risk of being affected by oral cancer, whereas the corresponding number for women is 2.3. The rates of tobacco use and alcohol consumption have recently increased among women, which is significantly changing the current rate of women oral cancer [28]. Due to the difference in lifestyle of men and women, the influence of other risk factors on oral cancer and potentially malignant lesions remains unexplained [44]. There may be some undiscovered factors. There is a fluctuation in women's oral cancer rate and tumor occurring site, although men have consistency, which lifestyle alone can not explain [44]. Diabetic and underweight individuals were found to be at increased risk of oral potentially malignant lesions [26].
