4. Discussion
This review highlights the extensive amount of research that has been conducted to investigate multiple mechanisms related to ESCC etiology in China. The most investigated risk factors were genetically related, followed by diet and dietary habits, HPV, gene-environment interactions, oral health, family history, H. pylori, and socioeconomic factors.
Almost 70% (68.11%) of included studies investigated genetically related etiologies of ESCC, among which most investigated genetic polymorphisms. The most investigated polymorphism was that on the TP53 gene. The TP53 gene encodes p53, which primarily functions as a tumor suppressor protein, which plays a critical role in cancer development [
85,
86]. TP53 mutation is the most occurring mutation found in human cancer, with over 50% of cancers holding mutations in the TP53 gene [
87]. TP53 mutation leads to p53 loss of functions that are needed to prevent tumor growth, which can lead to cell multiplication and cancer development [
88,
89]. Because of TP53’s role in cancer development, much research has been conducted looking at TP53 mutations and associations with ESCC. In addition to TP53 polymorphisms, the genetic variations included in this review include SNPs of over 151 unique genes, gene deletions, loss of heterozygosity, missense point mutations, and other genetic variations. Based on the extensive evidence of genetically related risk to ESCC shown in Supplementary materials,
Table S1, it is clear that there is a genetic influence on ESCC risk. However, due to the heterogeneity of studies, it was challenging to compare the influence of many different genetic variations measured across studies in a variety of regions, and a meta-analysis was not performed. A meta-analysis may be merited, however, in the future, if more evidence of the same genetic variations becomes available in comparable populations.
The significant portion of studies identified in this review that focused on genetically related etiologies underscores the importance of genetic susceptibility in advising public health prevention and intervention measures. These measures include genetic screening, early detection, personalized prevention strategies, targeted intervention, and public education and awareness. Genetic screening of polymorphisms in high-risk populations could identify genetic mutations associated with increased ESCC risk, could encourage individuals at high risk to be more proactive about endoscopic screening for early cancer detection when treatment outcomes are more favorable, and could provide eligibility information for potential gene therapy interventions. Because most cases are identified in late stages [
90], more emphasis on early screening, both genetic and endoscopic, prevention, and public education and awareness is imperative. Guidelines for practitioners for advising individuals carrying high-risk mutations, e.g. TP53 mutations, should be developed and readily/widely available. Guidelines might include younger, more frequent, and more aggressive cancer screening for individuals at higher risk. Policies should be implemented to fund genetic screening in high-risk populations. This review highlights the need for genetic susceptibility screening and the potential for more targeted intervention based on genetic risk factors of ESCC to be prioritized, especially in Chinese communities with significantly higher mortality rates of ESCC such as in Linzhou. Although genetic susceptibility was the most frequently researched etiologic factor identified in this review, its influence relative to and interaction with other factors is still unknown. Therefore, a comprehensive approach that measures genetic as well as other factors is crucial for effective public health ESCC intervention and prevention.
In addition to the extensive investigation of genetically related risk factors, this review also delved into other critical aspects contributing to ESCC risk, encompassing gene-environment interactions, family history, diet, dietary behavior, environmental-related risk factors, H. pylori, HPV, oral health, and socioeconomic factors. Many of these studies relied on retrospective qualitative data gathered through interviews, which carries the potential for recall bias. Despite these limitations, many studies identified significant associations.
The twelve studies that focused on gene-environment interactions highlighted in this review (Supplementary materials,
Table S2), particularly the studies that found associations that increased ESCC risk by almost 17 [
26] and more than 22 [
27] times, emphasize the significance of gene-environment interactions in ESCC development. Genetic polymorphisms or genetic changes can affect one’s susceptibility to environmental exposures and vice versa. For example, the increased risk from the positive multiplicative interaction between an XRCC1 polymorphism and consuming long-term stored rice, found by Yang et al., may suggest that the dietary habit of consuming long-term stored rice may worsen the effects of an XRCC1 polymorphism affecting DNA damage repair. This may lead to a synergistic effect on the development of ESCC, meaning that the combined effects of both factors are greater than the sum of each of their individual effects. Another example is the cumulative interaction between short leukocyte telomere length, smoking, and alcohol consumption found by Pan et al. This finding may suggest that smoking and alcohol consumption could cause oxidative stress, which would further impact individuals with shorter telomeres, further exacerbating the risk of all individual effects when combined. Additionally, the interaction between the Thymidylate synthase low expression genotype and low serum folate concentration reported by Tan et al. [
27] may suggest that consuming low amounts of folate may make DNA damage from the Thymidylate synthase polymorphism worse, leading to increased ESCC risk. This presence of a complex interplay between environmental exposures and genetic susceptibility in ESCC development suggests that a comprehensive approach to cancer prevention that includes genetic susceptibility, gene-environment interactions, and other etiologic factors is needed for effective ESCC mitigation. By incorporating information about gene-environment interactions into public health education programs, public health authorities can raise awareness about the complexity of cancer development and encourage individuals to be more proactive about reducing their risk to ESCC.
Three studies in this review reported family history as a potential ESCC etiologic factor, but because of the complexity of family history, concluding family history alone is challenging. Family history as an etiology of any disease can mean one’s risk might be affected by inherited genetic variations, similar living environments or lifestyles as family members, or both, and therefore contains many different factors. Only 7% of the studies included in this review adjusted for family history in their study; the lack of higher adjustments or considerations for family history makes sense as family history can mean a range of influencing factors, which makes it challenging to adjust for. Additionally, because most studies do not have exposure information of relatives, it’s challenging to distinguish the influence of environmental factors from genetic influence. Instead of family history as an etiologic factor, considering genetic, environmental, and the interaction between them may provide more insight into ESCC development.
Multiple studies identified alcohol and tobacco as potential risk factors in Jiangsu, Shandong, Hebei, and Gansu, among other provinces, and many studies acknowledged alcohol and tobacco consumption as well-established risk factors and adjusted for them in their analyses. Despite this evidence, a study conducted in Linzhou (formally known as Linxian), in 1989, which at the time had ten times higher rates of esophageal cancer mortality than China’s average, and still has one of the highest ESCC mortality rates in the world today, reported close to zero tobacco and alcohol consumption among females, little alcohol consumption in males, and only slightly higher tobacco usage among male ESCC cases compared to controls [
91] (study was not included in this review because it did not report ESCC-specific data). This review identified multiple studies that found alcohol and tobacco, and interactions with them, as contributing to ESCC development. However, this may vary by region, lifestyle, and culture. Further research including community dietary studies and risk factor comparisons by region may help address the role of alcohol and tobacco relative to other potential etiologies. Public health efforts should prioritize recognizing esophageal cancer as a heightened risk associated with tobacco and alcohol use, especially in high-incidence ESCC regions. Promoting greater public awareness of the link between alcohol and tobacco use and esophageal cancer is advisable, as well as the implementation of stricter tobacco and alcohol control measures, alongside the provision of well-funded, accessible programs for tobacco and alcohol use reduction.
Frequently consumed in high-risk areas of China, pickled vegetables and salted meat were reported by multiple studies in this review to be associated with ESCC etiology. The pickling of vegetables via fermentation and curing meats via the addition of nitrite or nitrate salts can produce N-nitroso compounds [
60] or mycotoxins,[
58] both considered carcinogens.[
92,
93,
94] It’s also possible that consuming high amounts of salt could lead to esophageal tissue injury, which could increase esophageal cancer risk through repeated esophageal injury, and that consuming high amounts of pickled vegetables could contribute to gastric atrophy, another risk factor identified in this review, through mucosa inflammation from repeated high-acid pickled vegetable consumption. Not all studies identified in this review identified pickled vegetables and salted meat as risk factors. As with many dietary studies, this inconsistency between studies could stem from dietary questionnaire recall bias, poor questionnaire design, or little reported variation between individuals’ dietary habits. The evidence suggests further exploration into diet culture in high-risk areas is imperative, particularly by comparing them with drastically lower ESCC incidence, such as the contrast between the high-incidence areas of Linzhou and adjacent lower-incidence areas. Furthermore, considering the possibility of contamination of various origins such as water, air, soil, and sharp micro contaminants e.g. silica or microplastics, adds further complexity to dietary-related risk factors. Accordingly, environmental health assessments should be conducted to further assess food contamination and safety. Through exploring dietary culture as well as environmental health factors, public health authorities can implement tailored interventions that promote healthier dietary choices to reduce ESCC risk. These interventions might include educational campaigns on higher-risk foods and policies to reduce consumption of pickled and salted foods. Such holistic efforts hold the potential to improve food safety and reduce ESCC risk.
Consumption of hot food or drink was identified in eight studies as a potential ESCC etiologic factor. Very hot beverages are designated as Group 2A carcinogens for ESCC by the IARC monographs, although they mention that the evidence in humans is limited [
93]. A few potential mechanisms of hot food or drink increasing ESCC risk are through physical esophageal damage leading to chronic inflammation of the esophageal mucosa, or the reduced ability of the mucosa to prevent exposure to carcinogenic substances, and the carcinogens themselves increasing risk to ESCC. Also identified in this review were multiple studies investigating tea consumption as a potential etiologic factor, with a range of outcomes. Among the studies that identified tea consumption as a risk factor, a potential mechanism could be a thermal injury. Other potential mechanisms include exposure to contaminants (e.g. mold) from fermented tea (black tea) old tea (some tea is intentionally consumed after prolonged storage) or water contamination. Current evidence suggests a further review of hot food and beverage consumption, as well as tea consumption, as risk factors of ESCC, as well as a comprehensive exam of potential mechanisms involved, such as thermal injury, change of salivary gland action, or exposure to contaminants. Additionally, it is critical to further develop targeted public health interventions, such as reducing high-temperature food and drink consumption.
HPV has been heavily investigated as a potential ESCC etiologic factor because of the extensive evidence of HPV’s association with cervical cancer [
95,
96]. In terms of ESCC etiology, it has been proposed that some proteins made by HPV, especially E6, are oncoproteins that can inactivate host proteins, namely p53, and may cause mutations in host cell DNA and lead to ESCC [
97]. Across eleven studies in this review, there was a wide range of HPV-positive prevalence rates reported among various provinces in China. Among the studies that looked at the association between HPV and ESCC risk, some studies found increased risk to ESCC, and others did not. This mixed level of detection, and lack of trends among associations, may point to a true lack of HPV prevalence in ESCC tissue and its limited evidence as an etiologic factor, but could also be due to the varying methods in sample processing or detection (e.g. PCR-based assays or serological tests), varying viral loads in ESCC samples and controls, regional differences, and other confounding factors that include alcohol or tobacco use. The presence of HPV in ESCC tissues, and the significant associations found in some studies, though limited, underscores HPV as a potential ESCC etiologic factor. More research is needed to further understand HPV's impact on ESCC risk and its mechanisms, as well as to inform early ESCC detection efforts e.g. HPV vaccination strategies, and any related regional disparities.
Additional environmental factors were explored in four studies. Two of the studies identified siliceous prickles resembling prickle hair from wheat bracts, in ESCC tissues [
81,
82]. Sharp micro-silica could potentially physically damage esophageal tissue and even provide a physical attachment point for cancer cell proliferation. Silica fibers could come from prickle hairs in wheat flour or wheat products as proposed in the two mentioned studies or could come from other sources entirely as silica is found in many foods and naturally in the environment. Additional environmentally related evidence identified in this review includes river water consumption as a risk factor [
24], and urinary exposure to N-nitrosamines [
83]. The available research on environmental factors associated with ESCC in China is limited but suggests that further investigation is warranted due to the potential impact of environmental exposures on the development of ESCC.
Several studies in this review reported that poor oral health, such as tooth loss, teeth brushing frequency, and oral bacteria diversity, may increase ESCC risk. Poor oral health could also play a role in ESCC development by increasing one’s risk for gastric atrophy, changing oral bacteria that affect how orally exposed carcinogens are digested, and increasing local and systemic body inflammation, leading to increased ESCC risk. These studies, four of which were conducted in Jiangsu, used questionnaires as some or part of their method of assessing oral health, which comes with recall bias. Additionally, the identified associations could also be confounded by diet or socioeconomic hardship (e.g. lack of access to dental care, or overall healthcare access as a whole), amongst other factors. For example, Abnet et al.’s study [
98] reported an increased risk of ESCC associated with tooth loss but did not address the potential reasons behind the tooth loss, which makes it hard to differentiate whether tooth loss itself increased ESCC risk, or if other factors increased ESCC risk and also contributed to tooth loss. Given these limitations, studies identified in this review suggest there is a link between poor oral health and ESCC. Public health education around improving oral health should be prioritized in high-risk communities to reduce ESCC risk.
Socioeconomic status (SES) factors, such as education level, household size, or appliance ownership, were also highlighted in multiple studies as potentially affecting ESCC risk. This makes sense, as SES indicators together may contribute to disease risk. For example, individuals who have received more formal education may have higher income opportunities, which may come with access to more frequent medical care, and earlier cancer detection. Individuals with more formal education may also have selectively higher access to endoscopic screening for ESCC and may therefore more frequently get screened. Many of the diet and lifestyle factors may be influenced by SES. As addressed in multiple studies, the importance of SES factors in disease development, including ESCC, is significant. Further efforts should be made to prioritize research into finding more SES factors that may influence ESCC development and allocating resources to mitigate those.
This review has several limitations. Only studies published in English were included in this review, which could underestimate or inaccurately represent the past or current research in China. Additionally, search terms used for the literature search were chosen to broadly encompass most research in the field, however, the search terms chosen could have also limited the studies included. Some studies included in this review did not account for the cancer history of all their study participants, or the history of cancer in study participants’ families, which could confound some of the study outcomes. Furthermore, the reported findings from each reviewed study do not include all results reported by each study, but instead include the most relevant and statistically significant results (p < 0.05) as decided by the reviewer; therefore, there are additional factors reported in these studies that may contribute to or be associated with ESCC risk. Also, there was one reviewer for this study which comes with inherent bias. Lastly, as this was a qualitative review of studies based on inclusion and exclusion criteria, this comes with some inherent selection bias of studies to some extent.