Cancer Etiology and Prevention Principle: “1 + X”

International Agency for Research on Cancer (IARC) of World Health Organization (WHO) released the latest global cancer report for 2020. There were an estimated 19.29 million new cancer cases and 9.96 million cancer-related deaths worldwide in 2020, with a 51.8% mortality rate, making cancer one of the leading death causes globally (1). In the early to middle 20th century, cancer was considered as the “terminal disease” or “incurable disease” inextricably linked with desperation, high medical expenses, and inevitable deaths. However, years of study on cancer epidemiology, etiology, pathogenic mechanisms, drug discovery, and clinical trials have decreased certain types of cancer incidence in the United States and most developed countries, and increased the therapy options and survival rate of patients with cancer. This is due to the more and more in-depth understanding of cancer etiology and improvements in cancer prevention to a great degree. A critical event in cancer research is the National Cancer Act signed by President Richard Nixon in 1971, elevating the importance of cancer research to the level of nuclear energy and space exploration. Since then, the war against cancer has been fruitful and marked by many landmark discoveries. The mean 5-year survival rate of patients with cancer in the United States is currently 70% compared with 49% 50 years ago (2). Insights into key risk factors associated with carcinogenesis have spurred initiatives aimed at minimizing their respective dangers to the public. For example, evidence linking cigarette smoking with lung cancer development has prompted multiple state governments across the United States to pass legislature to increase public awareness of the dangers associated with smoking and banning indoor smoking in public venues. The primary reason for the reduction of lung cancer incidence and mortality rates in the United States is the steady decline in smoking rates. On the other hand, no clear etiologic factor has been proposed for certain cancers. Importantly, stratification of the factors into a hierarchy based upon relative importance has been proven to be a nontrivial endeavor. Thus, efforts to decrease incidence and mortality rates of these nonclear etiology cancers have not been as successful as those with clearly defined primary risk factors. Here, we propose the “1 + X” principle for cancer etiology and prevention, “1” denotes the primary risk factor for a cancer in a particular geographic region and “X” represents the secondary risk factors for a specific cancer type. In this review, we elaborate upon the “1 + X” principle for cancer etiology and prevention with respect to several different cancer types, including lung, stomach, liver, colorectal, pancreatic, prostate, breast, cervical, skin, nasopharynx, oral, and esophageal cancers. The “1 + X” principle may serve as a general guide for cancer prevention, which would likely reduce cancer incidence and mortality rates worldwide.

The success of reducing the major cancer incidence rates enables us to propose the cancer etiology and prevention principle: “1 + X.” In this principle, one primary risk factor promotes tumorigenesis and progression, denoted by the “1,” and other contributing risk factors accelerate the cancer development, represented by the “X.” It is predicted that the global cancer incidence rates and mortality rates would dramatically decrease once the primary risk factor is eliminated, and the contributing risk factors are minimized. The “1 + X” principle will be used for precise prevention of cancer, which can accurately target the main cause of a cancer and then block it, and prevent contributing factors at the same time. In this way, we can improve the survival time of patients with cancer and reduce the global burden of cancer more effectively. The weakness may include that in certain cancers, the “1” or “X” is not well identified and thus may be difficult to prevent or control the particular cancer.

Lung cancer was responsible for 1,796,144 (18%) deaths worldwide in 2020 and is currently ranked the first and second in terms of mortality and incidence rates, respectively. Several factors implicated in lung cancer development and progression have emerged over the course of epidemiologic investigations spanning the 20th century and the first two decades of the 21st century. The rise in lung cancer rates was first observed in the 1920s and 1930s (3, 4). The first major evidence of the health effects of smoking in modern history came in 1950. Later it was confirmed that the increased mortality of smokers was related to the number of cigarettes they smoked in 1954 (5, 6). In 1990, the U.S. Surgeon General declared that smoking was the most widespread cause of lung cancer and other diseases ever investigated (7). Since then, interventions designed to increase public awareness of the dangers associated with smoking, alongside the banning of smoking in public venues, have resulted in significantly decreased lung cancer incidence and mortality rates. The National Health and Medical Research Council (NHMRC) of Australia observed a 30% increased lung cancer risk in nonsmoking individuals living with smokers and compared with smoker-free households in 1997. And second-hand smoke exposure is estimated to have caused 603,000 deaths, including 47% of deaths in women, 28% in children, and 26% in men, among them, 21,400 deaths (3.5%) resulted from lung cancer (8). The risk of lung cancer has prompted many smokers to utilize cessation aids such as patches, gum, and electronic cigarettes (e-cigarettes). While nicotine patches and gum are generally thought to pose a negligible health risk to consumers, it was reported that mice exposed to e-cigarettes for 54 weeks developed lung adenocarcinomas (22.5%) and bladder urothelial hyperplasia (57.5%), indicating that e-cigarette smoking may contribute to lung and bladder cancer in human (9, 10). With a possible 20-year lag in the potential carcinogenic effects of e-cigarettes, e-cigarettes could have a major impact on public health in the future (11). Other tobacco products including pipes, cigars, and water pipes have also been associated with increased lung cancer risk and mortality rate (12). An analysis based on the data from the National Longitudinal Mortality Study and the Tobacco Use Supplement of the Current Population Survey assessed the risk of lung cancer–related death among 357,420 individuals who were never, current, or former users of cigarettes, cigars, and pipes. The results of the study indicated that the risk of lung cancer–related death was highest among daily cigarette smokers (12.7-fold increased risk), followed by daily cigar smokers (4.2-fold increased risk), and daily pipe smokers (1.7-fold increased risk; ref. 13). Additional meta-analysis and cohort studies reported that pipe use was associated with a 1.9- to 4.6-fold increased risk of lung cancer and cigar use with a 2.7 to 2.95–fold increased lung cancer risk (14–16). Collectively, these studies suggest that cigarette smoking is the primary risk factor for the development of lung cancer and that second-hand smoke, e-cigarette use, and the use of other tobacco products are secondary risk factors.

Although smoking has been widely implicated as a major risk factor for lung cancer, approximately 25% of lung cancer cases are not associated with tobacco use and cause more than 300,000 deaths each year. Epidemiologic studies of lung cancer in never smokers (LCINS) have identified obvious gender, age, and geographic variations, with a susceptibility to women regardless of geographic location. Strikingly, nearly 83% of women with LCINS are located in East and South Asia, compared with the 15% located in the United States (17). Additionally, the proportion of LCINS is higher in old-age people than that in younger people (<40 years, 4%; >70 years, 11.2%; >80 years, 17.2%; ref. 18). Many other risk factors have been elucidated for lung cancer development, including genetic susceptibility, occupational exposures, dietary habits, infections, and inflammatory diseases (Fig. 1; Supplementary Table S1). Various genomic alterations have been reported more predominantly in lung cancer compared with other cancer types. EGFR, proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase (ALK) fusions occur in a large proportion of patients with LCINS, while v-Ki-ras2 Kirsten Rat sarcoma viral oncogene homolog (KRAS), serine/threonine-protein kinase B-raf (BRAF), tumor suppressor (TP53), tyrosine-protein kinase JAK2 (JAK2), tyrosine-protein kinase JAK3 (JAK3), and mismatch repair gene mutations have been observed more frequently in patients with lung cancer with a history of smoking. Furthermore, the C:G → A:T transversion predominantly occurs in smokers, whereas the C:G → T:A transition is most frequently detected in nonsmokers. The KRAS gene is mutated in approximately 30% of lung adenocarcinomas, 25% of non–small cell lung carcinomas (NSCLC), and 5% of squamous cell lung carcinomas (19). The frequency of EGFR mutation in lung cancer ranges between 40% and 70%, and occurs most frequently in nonsmokers. Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of NSCLC cases, however, gene amplification and gene mutations of HER2 are observed in approximately 2% to 6% of lung adenocarcinomas (20, 21). Moreover, HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC (20). Oncogenic fusion genes including echinoderm microtubule-associated protein-like 4 (EML4) and ALK have been observed in a subgroup (2%–7%) of NSCLC (22). The EML4-ALK translocation is an important clinically relevant mutation that occurs in approximately 3% to 11% of NSCLC cases and is frequently observed in female patients with LCINS (23). The discovery of ALK rearrangements in 3% to 7% of NSCLC cases in 2007 expanded the range of targeted genomic changes (24). Since then, several other driving events with strong transformational potential have been described, including oncogenic ROS1, RET (proto-oncogene tyrosine-protein kinase receptor Ret), NTRK1 (high affinity nerve growth factor receptor), and NRG1 (transcriptional regulator NRG1) fusions, oncogenic mutations in BRAF (V600E and non-V600E), HER2 intragenic insertions, and MET proto-oncogene exon 14 skipping mutations. In a 1,073 tumor screen, 1.7% tumors harbored rearranged ROS1 in the younger patients, and they were more likely to be nonsmokers compared with the ROS1-negative group. Additionally, all the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade (25). The in-frame fusion of the kinesin family 5B gene (KIF5B) and RET oncogene occurs in 1% to 2% of lung adenocarcinoma, which leads to aberrant activation of RET kinase and is considered a novel driver mutation (26). BRAF V600E mutations were found in 2% to 4% of NSCLC patients (mainly adenocarcinoma), and were more common in smokers than nonsmokers (27). MET is frequently overexpressed, activated, and sometimes mutated in lung cancer, which suggests that it may be a promising target for lung cancer treatment (28).

Occupational exposure is an important risk factor for lung cancer and the IARC has listed 19 substances/work situations/occupations [group 1: tars, pitch, soot, schist and bitumen; arsenic; asbestos; beryllium; bis (chloromethyl) ether and chloromethyl methyl ether; cadmium; hexavalent chromium; mists and vapors; painter (metals, antirust agent, and resins); leather industries; coke production (polycylic aromatic hydrocarbons; PAH); aluminum production (PAHs); iron and steel production (PAHs); mustard gas; coal gasification (PAHs); nikle; rodon; crystal silica; talc with asbestiform fibers] that have been proven to correlate with lung cancer (29). Residential radon was reported to increase lung cancer risk with concentrations more than 200 Bq/m³ [objective response (OR) 2.06, 95% confidence interval (CI) 1.61–2.64] compared with less than 50 Bq/m³, and lung cancer risk increases dramatically upon combination of smoking with exposure to heightened concentrations of radon (heavy smokers exposed to more than 200 Bq/m³: OR 2.06, 95% CI 15.4 - 55.7), which causes about 21,000 deaths from lung cancer each year (30). It was reported that 0.8% and 2.4% of lung cancer was attributed to radon and occupational diesel engine exhaust exposure in Canada, respectively (31, 32). The association between asbestos exposure and lung cancer risk is linear, but may plateau at very high exposures (33). The IARC specifically identified outdoor air pollution and airborne particles as human carcinogens in 2013 (34). A Korean National Health Insurance Service Health Examinee Cohort Study reported that long-term exposure to air pollution was associated with an elevated risk of lung adenocarcinoma in male smokers (35). Other studies reported that the interaction between smoking and air pollutants increased lung cancer risk. Specifically, heightened PM 2.5 level can affect lung adenocarcinoma incidence and patient survival (36, 37). Household air pollution was identified as a risk factor of lung cancer in women (38, 39). Fumes produced during cooking have been suggested as risk factors for female LCINS. One study reported that lung cancer risk was correlated with cooking fume exposure in a dose-dependent manner and that long-term use of a fume extractor during cooking could reduce lung cancer risk by nearly 50% (40, 41). Moreover, cooking habits, consisting of cooking methods and oil use, were associated with lung cancer risk.

Dietary habits play an important role in altering cancer risk, including lung cancer. There is a convincing link between high intake of red meat and cancer, especially with respect to colorectal, lung, prostate, breast, esophageal, and gastric cancer. In contrast, a diet supplemented with vegetables, fruits, nuts, fish, soy, vitamin B, vitamin C, vitamin D, vitamin E, and zinc was shown to confer a protective effect on lung parenchyma (42, 43). Several studies have indicated that virus infections are closely correlated with lung cancer. It was reported that human papillomavirus (HPV) was detected in 52.38% of lung tumor tissues, with HPV 16 and HPV 18 being detected at frequencies of 81% and 19%, respectively. Specifically, HPV was detected in 39.39% of squamous cell lung carcinomas, 33.33% of lung adenocarcinomas, 18.18% of small cell lung carcinomas, and 9.1% of large cell lung carcinomas. Moreover, E6 and E7 (anti-HPV 16 and anti-HPV 18) oncoproteins were detected in 84.85% and 75.76% lung tumor samples, respectively (44). Another report showed that the highest proportion of patients with HPV-positive lung cancer by region was in Latin America (33.5%), followed by Asia (31%) and European countries (18%). The highest occurrence of HPV 16 and HPV 18 infections was observed in Asia (40.3%), followed by Latin America (33.6%), Europe (25.6%), and North America (15.4%). HPV 6 and HPV 11 infections were predominantly observed in Asia (39.9%), followed by Europe (30%) and North America (12.8%; ref. 45). These findings suggest that HPV may play a key role in lung cancer development, however, additional studies are needed to further characterize their association. Lung cancer is the most frequent type of cancer-related death observed in people living with human immunodeficiency virus (HIV), and the overall survival time of patients with cancer infected with HIV is significantly shorter than patients without HIV infection (46). In addition, lung cancer occurs more frequently in patients living with HIV than in the HIV-negative population (47). A study conducted at the McGill University Health Centre between 1988 and 2018 reported that 78% patients who were HIV positive had a primary lung cancer, and 52% had metastatic disease upon diagnosis (48). However, HIV status may be an independent risk factor for lung cancer incidence and poorer outcomes when controlling for other factors.

According to the GLOBALCAN 2020, there were approximately 1.09 million new gastric cancer cases and 768,793 gastric cancer–related deaths, ranking them fourth and fifth among all cancers in terms of mortality and incidence rates, respectively. Nearly 75% of global gastric cancer cases are comprised of those living in Asia, followed by 12.5% in Europe. In 2020, 44% of new gastric cancer cases emerged in China, followed by 13% of cases in Japan. Helicobacter. pylori (H.pylori) infection is a well-defined gastric cancer risk factor. Barry Marshall, the researcher responsible for identifying H.pylori, successfully isolated and cultured H.pylori from gastric mucosa biopsy samples in 1982. In 1984, Barry Marshall and Robin Warren proposed a role for H.pylori infection in the pathogenesis of gastroduodenal disease (49, 50). As time progressed, subsequent studies provided evidences suggesting a link between H.pylori and gastric cancer development. Epidemiologic studies have shown that Asia has the highest proportion of gastric cancer cases attributable to infections, especially H.pylori infection. Among all Asian countries, China, Japan, India, and South Korea have the higher incidence rates of gastric cancer. However, gastric cancer incidence and mortality rates in Japan are decreasing, and the 5-year relative survival time in Japan has increased to nearly 81% (51, 52). The primary reasons for the declining incidence and higher 5-year survival rates of gastric cancer in Japan include H.pylori eradication, early diagnosis, and improved treatment strategies. H.pylori infection is estimated to affect up to more than half of the global populations and approximately 75% of the worldwide gastric cancer burden, and 5.5% of malignancies worldwide are attributable to H.pylori-induced inflammation and injury (53). The cumulative gastric cancer incidence rate at 5, 10, and 20 years after detection of H.pylori infection was 0.37%, 0.5%, and 0.65%, respectively (54). In general, it was found that extended wait times between follow up correlated with a greater risk of developing diffuse-type gastric cancer in patients infected with H.pylori that have experienced mild to moderate gastric atrophy (55). Factors associated with gastric cancer include older age at the time of H.pylori detection and smoking history. In addition, women had a lower risk of gastric adenocarcinoma compared with men. Patients undergoing H.pylori treatment still had an increased risk of gastric cancer, but successful H.pylori clearance reduced risk and deaths of gastric cancer. Moreover, H.pylori eradication can also reduce incidence of gastric cancer in patients with gastric neoplasia (56, 57). The IARC of WHO has classified H.pylori infection as a class I carcinogen for gastric cancer, especially for people over 40 years old. H.pylori infection can induce the classical Correa's gastric carcinogenesis cascade from normal mucosa, gastritis, to carcinoma. Currently, there are no clinically effective drugs for treating chronic gastritis, which promotes the transformation process to gastric cancer. An analysis of population attributable fraction of H.pylori infection-related gastric cancer in South Korea reported that the estimated prevalence of H.pylori infection was 76.4% in men and 71.9% in women (58). Another study reported that the overall prevalence of H.pylori infection was 38.5% to 45.9% among patients with gastric cancer, conducted at the Houston VA Hospital (2007–2018) in America, and the proportions of H.pylori-positive gastric cancer decreased from 50.0% (2007–2010) to 43.4% (2011–2014) and 29.3% (2015–2018; ref. 59). Active/acute gastritis (OR 3.74), atrophic gastritis (OR 15.30), and gastric intestinal metaplasia (OR 3.65) were associated with H.pylori-positive gastric cancer. These findings indicate that other risk factors may influence the occurrence of gastric cancer in addition to H.pylori infection, which may increase gastric cancer incidence.

Epstein–Barr virus (EBV) is an oncogenic human herpes virus associated with gastric cancer development and is estimated to contribute to approximately 10% of gastric cancer cases. EBV-associated gastric cancer has characteristic clinicopathologic features with a proximal location in the stomach, lymphoepithelioma-like histology, predominance among males, and a favorable prognosis proven by numerous studies over the past 30 years. It was reported that patients with EBV-positive gastric cancer accounted for 4.1% (55 of 1,328) of gastric cancer cases, these patients tended to have low-differentiated adenocarcinoma characterized by minimal vascular invasion and increased infiltration of multiple immune cells, especially CD3⁺ T lymphocytes (60, 61). Another Peruvian study reported that 8.4% of gastric cancer cases were EBV positive, and most tumors were localized in the antrum/pylorus of older (>60 years old) males with a tendency toward better prognostic (62). The molecular mechanisms associated with EBV-positive gastric cancer mainly include inflammatory changes in gastric mucosa, host immune evasion by EBV, modulation of cell-cycle pathways, hypermethylation of tumor suppressor genes, regulation of miRNAs, and overexpression of programmed death ligand 1 (PD-L1; ref. 63). The coexistence of H.pylori and EBV in gastric cancer specimens has been increasingly reported. The overall prevalence of H.pylori and EBV coinfection in nonmalignant gastroduodenal disorders (gastritis, peptic ulcer disease, and dyspepsia) was 34% (ranging from 1.8% to 60%) in Latin America and India (64). Moreover, H.pylori and EBV coinfection was associated with increased severity of gastric inflammation than gastritis caused by infection with either single pathogen alone.

An increasing number of studies have suggested that certain individuals may be genetically predisposed to developing gastric cancer. One Finnish study reported that gastric cancer risk was associated with gastric cancer history in first-degree relatives overall, in fathers, and in siblings. The observed associations were significant for noncardia cancers, and marginal for both intestinal and diffuse-type histology (65). Another study reported that the gastric cancer incidence was 1.2% in the H.pylori treatment group (lansoprazole, 30 mg; amoxicillin, 1,000 mg; and clarithromycin, 500 mg, each taken twice daily for 7 days) and 2.7% in the placebo group. And 50% of participants had persistent H.pylori infection among the participants in the treatment group in whom gastric cancer developed, 0.8% in whom H.pylori infection was eradicated, and 2.9% in whom had persistent infection in a single-center, double-blind, placebo-controlled trial with first-degree relatives of patients with gastric cancer during a median follow-up of 9.2 years. The results indicated that for individuals with H.pylori infection who had a gastric cancer family history in first-degree relatives, H.pylori eradication treatment could reduce gastric cancer risk (66). In a study of 1,805 patients with gastric cancer who underwent curative gastrectomy in 2000 to 2008 in China, it was reported that gastric cancer was correlated with positive gastric cancer family history, age, alcohol, and tobacco use in 21.2% of patients (67).

Heavy alcohol consumption was proven to be a risk factor for gastric cancer. It was reported that heavy drinking (more than 7 times a week) and binge drinking (more than 55 g alcohol intake per occasion) showed a 3.48-fold and 3.27-fold, respectively, higher risk in H.pylori-negative subjects compared with nondrinking populations (68). However, there is a lack of association between moderate alcohol consumption and gastric cancer risk. The association between gastric cancer and alcohol consumption is stronger in East Asians than in other ethnic groups, presumably due to the aldehyde dehydrogenase 2 (ALDH2) polymorphism. One South Korean study revealed that the risk of gastric cancer was higher in men with the inactive ALDH2 (GG) than in those with active ALDH2 (GA/AA), whereas no significant association was found in women. Moreover, the association between ALDH2 genotype and gastric cancer risk was stronger in men that regularly consumed alcohol (69, 70). Our group reported that alcohol (5 g/kg/day) combined with H.pylori infection could induce gastritis and gastric tumorigenesis in CB/57 mice (71). More detailed evidence is needed to elucidate the relationship between gastric cancer and alcohol consumption. Tobacco smoking is considered as another risk factor for gastric cancer. The risk of gastric cancer is increased for heavy (>20 cigarettes per day) and long-term (>40 years) smokers. Interestingly, the risk for developing gastric cancer in cigarette smokers decreases upon cessation, exhibiting similar rates to that of never smokers after achieving 10 years after stopping of abstinence (72). In addition, unhealthy lifestyle such as stress and physical inactivity are correlated with increased gastric cancer risk. It was reported that longer refrigerator ownership was associated with a 67% decreased risk of gastric cancer in the H.pylori-negative group and that tea consumption dramatically decreased gastric cancer risk in a high-risk region of Chinese population (73). Data from epidemiologic, experimental, and animal studies revealed that diet plays a critical role in the etiology of gastric cancer (Fig. 1; Supplementary Table S1). High intake of nitrosamines, salt and salted foods, meat or processed meat products, and overweight/obesity are associated with increased gastric cancer risk. In contrast, high intake of fresh fruits and vegetables, vitamin C, selenium, nuts, and lycopene or lycopene-containing food products may reduce gastric cancer risk (74, 75). Gastric cancer was previously considered to be an age-related disease, with one example indicating that the majority of new cases in the United Kingdom diagnosed over the age of 75 (76). However, several studies have suggested that gastric cancer incidence is increasing in young adults, especially for noncardia gastric cancer. One study identified that the incidence of gastric cancer is rising the highest among young Hispanic men in the United States (77). Alarmingly, these findings suggest that the gap of gastric cancer risk between the older and younger populations is narrowing.

There were approximately 905,677 (4.7%) new cases of liver cancer and 830,180 (8.3%) liver cancer–related deaths in 2020. Liver cancer ranked to the sixth and third in terms of incidence and mortality rates, respectively. In addition, the 5-year survival rate of liver cancer remains low. Geographically, Asia had the highest liver cancer burden, which accounted for more than 72.5% of all cases, followed by Europe (9.7%) and Africa (7.8%). Epidemiology and etiology studies have revealed that hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, alcohol consumption, nonalcoholic fatty liver disease (NAFLD), and aflatoxins/aristolochic acid exposure are risk factors of primary liver cancer (Fig. 1; Supplementary Table S1). In 1965, Blumberg and Alter discovered a protein in the serum of an Australian Aboriginal that could produce an antigen–antibody reaction in the serum isolated from patients with leukemia (78). It was later discovered that this protein was the surface antigen of HBV. In 1971, the entire virus was isolated, revealing the surface and core of the virus. Further research showed that the E antigen of HBV, the core of the virus, is associated with infection (79–81). Chronic HBV and HCV infection are the main factors of liver cancer, and patients may develop liver cancer after 25 to 30 years of HBV infection at a rate between 20 and 100 times higher than uninfected individuals (82, 83). Between 2015 and 2030, it was estimated that 257 million people will be infected with HBV, and 57 million people will be infected with HCV worldwide. HBV infection is the primary risk factor for liver cancer in most developing countries, while HCV infection is the main cause of liver cancer in developed countries. There were around 39.1% of deaths related to HBV-related liver cancer and 29.1% of deaths related to HCV-related liver cancer in 2017 (84). HBV-related liver cancer was more common in China, Thailand, Vietnam, South Korea, and India, which accounted for 80% of the global HBV-related liver cancer deaths. Deaths related to HCV-related liver cancer were more frequent in China, Indonesia, Japan, Italy, the United States, Brazil, Egypt, and India. China had the highest liver cancer incidence rate (45%) and mortality rate (47%) among all countries in 2020. Japan had the highest HCV-related liver cancer incidence (65.77%) and deaths (66.53%), while HBV-related liver cancer incidence and deaths accounted for 9.74% and 9.15% of the regional rates, respectively. Liver cancer incidence and mortality are highly correlated with gender and age, which occurs more frequently in males (three times than females) and older populations. It was reported that the mean ages of diagnosed patients increased from 57.14 to 60.34 years in males and 61.69 to 66.47 years in females from 1989 to 2008 in China (85). Hepatocellular carcinoma (HCC) accounts for more than 80% of primary liver cancers worldwide and is most common in patients with hepatitis with necrotizing cirrhosis (86). More than 80% of HCC cases occur in low/middle resource areas, especially in East Asia and sub-Saharan Africa. Maupas and Hilleman and colleagues obtained hepatitis B vaccine from plasma during 1975 to 1976 (87, 88). In 1978, Tiollais, and colleagues successfully developed a recombinant hepatitis B vaccine through genetic engineering (89). The hepatitis B vaccine is considered the first anticancer vaccine. From 1985 to 1995, the HBsAg carrier rate in the general population dropped from 9% to 1%. In 1998, the first direct-acting antiviral drug (lamivudine) for chronic hepatitis B was approved by the FDA (90). Through these advancements, the incidence of HBV-related liver cancer was significantly reduced, and childhood HCC was nearly eradicated.

Excessive consumption of alcohol results in the cirrhosis of the liver, which highly correlated with the development of liver cancer. Global prevalence of alcohol-associated compensated and decompensated cirrhosis was 23.6 million and 2.5 million, respectively, and approximately 15% of liver cancer–related deaths and incidences were caused by alcoholism in 2017 (91). Moreover, more than 30% of liver cancer–related deaths and incidence in Australia, Central Europe, Eastern Europe, and Western Europe were caused by alcohol consumption. One study reported that the risk of liver cancer is doubled in individuals who have consumed more than 80 g/day of alcohol for over 10 years compared with nondrinkers (92). Statistics have shown that the per capita alcohol consumption (more than 15 years old) in China rose from less than 2 L in 1981 to approximately 6.7 L in 2010 and will reach 8.3 L in 2025, which is likely coincide with increased incidence rates of liver cancer (93). Recently, a study reported that continuous consumption of more than a low-level of alcohol (1 drink/day for females or 2 drinks/day for males) is also related to a higher risk of liver cancer (94). These findings suggest that continuous alcohol consumption is a risk factor for liver cancer regardless of the dose or type of alcohol.

NAFLD affects more than 25% of the U.S. population and is a leading cause of chronic liver disease. More than 30% of liver disease and diabetes-specific deaths are associated with NAFLD (95). It is estimated that 25% of patients with NAFLD may have nonalcoholic steatohepatitis (NASH), which is associated with significant morbidity and mortality due to complications of liver cirrhosis, hepatic decompensation, and HCC. NAFLD and NASH have been identified as emerging risk factors for HCC. NAFLD and NASH prevalence was predicted to increase by 25% and 40%, respectively, and the incidence of deaths related to NAFLD-related liver cancer was estimated to increase by 85% from 2019 to 2030 in Australia (96). NAFLD is the most common liver disease and a major risk factor for HCC in most developed countries. It has been reported that NAFLD was associated with a 2.6-fold increased risk of HCC, and NAFLD-related HCC accounted for 10% to 20% of all HCC cases in the United States (97, 98). NAFLD-related HCC is more common in elderly patients (over 65 years) than younger patients and most frequently occurs in the absence of cirrhosis compared with virus-associated HCC (98, 99). Diabetes mellitus and/or obesity, major clinical risk factors for NAFLD, had the highest population-attributable fraction of 37% for HCC in the United States (100). Moreover, diabetes mellitus is associated with a 2- to 3-fold increased risk of HCC, even in patients with liver cirrhosis (101). NAFLD was also found to increase the risk of other cancers besides liver cancer. In a cohort study, NAFLD increased the risk of thyroid cancer and HCC in men with higher levels of alanine aminotransferase, colorectal and lung cancer in smokers, and kidney cancer in men without diabetes (102).

Aflatoxins are secondary metabolites produced mainly by the molds Aspergillus flavus, A. parasiticus, and A. nomius, which contaminate cereals, dry fruits, oilseeds, and spices. Aflatoxins have harmful effects and prolonged exposure of animals and humans may result in several cancers. There are two types of aflatoxins: aflatoxin B1 (AFB1) and aflatoxin B2 (AFB2), produced by A. flavus and A. parasiticus, respectively. Aflatoxin has been proven to be one of the major causes of HCC in developing countries. It was reported that the urinary AFB1 metabolites were detectable in 88.9% of samples in individuals from Zhuqing Village, Fusui County, an area with high HCC rates (64%) in China from 1973 to 1999 (103). A similar phenomenon was observed in a Hispanic community in Bexar County, Texas, in 2010 (104). Moreover, AFB1 and its metabolite aflatoxin M1 (AFM1) have been classified as group 1 and group 2B human carcinogens by the IARC. Popcorn was thought to be susceptible to aflatoxin contamination, which might increase liver cancer risk, requiring more verification (105). HBV infection was found to have a synergistic hepatocarcinogenic effect with AFB1 exposure (106). Aristolochic acid (AA) is an abundant compound in Aristolochia plants and various natural herbs. A weight-loss formula containing aristolochic, used in Belgium in the 1990s, was reported to cause kidney damage and bladder cancer. One study showed that mice exposed to AA developed liver cancers (HCC, combined HCC, and intrahepatic cholangiocarcinoma) in a dose-dependent manner. Moreover, an AA-associated mutational signature has been identified in human liver cancers (107). Another study reported that patients with HCC from Asia, particularly Chinese mainland (47%), Taiwan (78%), and Southeast Asia (29%) showed increased rates of the AA-associated mutational signature compared with reduced detection rates observed in patients with HCC from Japan (2.7%), North America (4.8%), and Europe (1.7%; refs. 108, 109). A dose-dependent correlation has also been shown between AA exposure and HCC risk in Taiwan (110). Patients who were HBV/HCV positive exposed to AA were reported to have an increased risk of developing acquired primary liver cancer (111). However, the use of preparations containing AA, such as many traditional Chinese medicines, remains controversial and warrants further investigation.

There were estimated 1,931,590 new colorectal cancer cases and 935,173 colorectal cancer–related deaths worldwide in 2020, ranking colorectal cancer the second and third in terms of mortality and incidence rates, respectively. The combined incidence rate of China (28.75%), the United States (8%), and Japan (7.7%) was around 44.5%. The risk of colorectal cancer is markedly increased in individuals over 50 years old. However, the incidence of early onset colorectal cancer (colorectal cancer in individuals under age 50) has been increasing by 2% per year since 1994, suggesting that the age gap with respect to colorectal cancer risk is shrinking. Etiologic studies elucidated that colorectal cancer is a multifactorial cancer type, meaning that there is no clearly defined primary risk factor as previously assumed. However, an increasing volume of epidemiologic and clinical evidences suggested that excess body mass index (BMI; obesity, BMI ≥ 30 kg/m²; overweight, 25 ≤ BMI ≤ 29.9 kg/m²) and excess high fat diet (HFD), especially red and processed meat might be the main risk factor for colorectal cancer. For example, studies have indicated that excess BMI was associated with a 30% to 70% increased risk of colorectal cancer in men (112, 113). Each 5 kg/m² increase in BMI was associated with a 17% (RR 1.17, 95% CI 1.09–1.25), 8% (RR 1.08, 95% CI 1.04 - 1.11), and 13% (RR 1.13, 95% CI 1.08 - 1.19) higher risk of colorectal cancer in men, women, and overall, respectively (114). Additionally, an estimated 17.7% of colorectal cancer cases were attributed to excess BMI worldwide in 2012 according to the WHO. Moreover, higher BMI leads to poor outcomes and increased colorectal cancer mortality (115). A systematic review reported that colorectal cancer risk is positively correlated with consumption of red and processed meats, high carbohydrate intake, sugar-sweetened foods, preserved foods, saturated or animal fats, cholesterol, and spicy foods. Inversely, soy bean or soy products, calcium or dairy foods, lycophene, vitamin C, D, E, and B12, selenium, vegetables, fruits, fiber, α/β-carotene, folic acid, green tea, isoflavones, and some minerals play protective roles against colorectal cancer, while the associations of fish and seafood with colorectal cancer risk are still inconclusive. Low vegetable/fruit intake and high red and processed meat intake attributed to around 30% of colorectal cancer. Possible biologic mechanisms for colorectal cancer include adipocytokines, insulin resistance, metabolic alterations, hyperinsulinemia, altered levels of growth factors, steroid hormones, chronic inflammation, bacterial dysbiosis, and diminished gut barrier integrity.

Extensive studies have reported that physical inactivity, unhealthy diets, smoking, alcohol consumption, and family history are important risk factors for colorectal cancer (Fig. 1; Supplementary Table S1). It was reported that physical inactivity was responsible for a substantial number of deaths (1990: 1,302; 2015: 119,351) and disability-adjusted life-years (DALY; 1990: 31,121; 2015: 87,116) due to colorectal cancer in Brazil, and the mortality and DALYs due to physical inactivity–related colorectal cancer increased in Brazil (0.6% and 0.6%, respectively) from 1990 to 2015 (116). Physical activity was shown to reduce colorectal cancer risk by 24%. Furthermore, increasing physical activity by 15 metabolic equivalent task hours per week after colorectal cancer diagnosis was associated with a 38% lower risk of death (117, 118). Smoking and alcohol consumption accounted for 4.9% and 5.4% of colorectal cancer in China in 2012 (119). A South Korean study reported that colorectal cancer risk dramatically increased for heavy smokers who smoked more than 40 packs/year (OR 1.74, 95% CI 1.22–2.50), more than 40 years (OR 1.50, 95% CI 1.05–2.16), or more than 40 cigarettes/day (OR 1.92, 95% CI 1.04–3.54) in males. Similar findings were observed in heavy female smokers who have smoked for more than 20 years (OR 3.21, 95% CI 1.27–8.14 for colon cancer) or more than 20 cigarettes/day (OR 4.75, 95% CI 1.09–20.57 for colon cancer, OR 6.46, 95% CI 1.64–25.46 for rectal cancer). Moreover, the same study indicated that consumption more than 40 g alcohol/day (OR 2.39 95% CI 1.68–3.41) in men and more than 20 g/day (OR 3.52 95% CI 1.56–7.96) in women were at an increased risk of developing colorectal cancer in South Korea (120). Individuals with a family history of colorectal cancer were at a high risk (OR 1.87 95% CI: 1.68–2.09) of colorectal cancer (121). Additionally, inflammatory bowel disease (IBD) and gene mutations (APC: APC regulator of WNT signaling pathway, KRAS, TP53, DCC: DCC netrin 1 receptor) are closely correlated with colorectal cancer risk. Effective primary prevention efforts for colorectal cancer include chemoprevention (low-dose aspirin), physical activity, limited alcohol consumption, reduced consumption of red and processed meat, and adequate intake of fiber, whole grains, and dairy products (Fig. 1).

There were estimated 495,773 new pancreatic cancer cases and 466,003 pancreatic cancer–related deaths worldwide in 2020, ranking it the 12th and the seventh in terms of incidence and mortality rates, respectively. In the United States, pancreatic cancer ranked 11th at the incidence rate and the third at the mortality rate, and the 5-year survival rate was less than 10%, that pancreatic cancer was called “the king of cancer” due to its high mortality rate. Pancreatic cancer occurs predominantly in men and at advanced age (40–85 years). Several epidemiologic, clinical, and in vivo studies have implied that smoking is a significant risk factor for pancreatic cancer, with an estimated 30% of pancreatic cancer cases being attributed to smoking. It was reported that the burden of pancreatic cancer in Australia was attributed to current and recent smoking by 21.7% (95% CI 13.8%–28.9%), and current smoking alone by 15.3% (95% CI 8.6%–22.6%) of future pancreatic cancer burden. Additionally, the burden attributable to current smoking is greater for men (23.9%, 95% CI 13.3%–33.3%) than for women (7.2%, 95% CI 0.4%–14.2%), as well as for those under 65 years old (19.0%, 95% CI 8.1%–28.6%) than for older people (6.6%, 95% CI 1.9%–11.1%; ref. 122). Moreover, this pancreatic cancer burden would be avoidable over 25 years if smoking activity ceased. Another study found that the pancreatic cancer risk was highest in current black smokers (OR 2.09, 95% CI 1.31–3.41), followed by blond smokers (OR 1.43, 95% CI 1.01–2.04; ref. 123). Furthermore, exposure to tobacco smoke during childhood was also associated with increased pancreatic cancer risk (OR 1.24, 95% CI 1.03–1.49; ref. 123). Mechanistically, cigarette smoking may promote pancreatic cancer development through several pathways, including excessive maturation of miR-25 to -3p through m6A modification, increased differentiation of myeloid-derived suppressor cells (MDSC), increased expression of heparin-binding epidermal growth factor (HB-EGF) in macrophages, activation of stem cell features via cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) signaling, FOS-like 1 (FOSL1) activation of RNA polymerase II–associated factor (PAF1), and specific genetic polymorphisms such as cytochrome P450 1A1 (CYP1A1; refs. 124–127).

Heavy alcohol consumption, obesity, diabetes, diets, and family history are contributing risk factors for pancreatic cancer (Fig. 1; Supplementary Table S1). High alcohol consumption increased pancreatic cancer risk in black men (OR 2.2 95% CI 0.9–5.6) and white men (OR 1.4 95% CI 0.6–3.2) who had more than 57 drinks/week. Pancreatic cancer risk was also significantly increased in black women, who had more than 8 drinks/week (OR 2.1 95% CI 0.8–5.9), compared with white women (128). Additionally, each 4.6 kg/m² gain in BMI was associated with increased pancreatic cancer risk (OR 1.34 95% CI 1.09–1.65; ref. 129). The contribution of obesity on pancreatic cancer may be attributed to insulin resistance, chronic inflammation, and altered intestinal microbiota. Approximately 80% of patients with pancreatic cancer with diabetes, showed a poor prognosis, suggesting diabetes may be correlated with pancreatic cancer (OR 2.96, 95% CI 1.48–5.92), although the detailed mechanism remains unclear. An HFD can significantly increase pancreatic cancer growth and metastasis, whereas vitamin D and green tea consumption may provide protective effects against pancreatic cancer (130). Additional positive risk factors for pancreatic cancer include family history, non-O blood groups, and gene mutations [cyclin-dependent kinase inhibitor 2A (p16), 95%; KRAS, 90%; TP53, 75%; SMAD family member 4 (DPC), 55%]. The most effective strategy for pancreatic cancer prevention is smoking cessation and exercise.

There were estimated 1,414,259 new cases and 375,304 prostate cancer–related deaths worldwide in 2020, raking it to the fourth and the eighth in terms of incidence and mortality rate, respectively. The United States had the most new cases of prostate cancer (14.8%) in 2020, and prostate cancer ranked to the third at the incidence rate and the fifth at the mortality rate in the United States. Prostate cancer occurs predominantly in elderly males (>65 years), however, more than 10% of new prostate cancer cases occur in young men ≤ 55 years in the United States. Alarmingly, rates of prostate cancer in individuals younger than 50 years have been increasing by 2% per year since 1990s. There are multiple risk factors for prostate cancer, including HFD, excess BMI, smoking, physical inactivity, alcohol, family history, smoking, ethnicity, insulin-like growth factor, sexually transmitted disease (STD), occupation, and vasectomy (Fig. 1; Supplementary Table S1). The link between diet and cancer has become increasingly prominent in recent years, with epidemiologic data showing differences in the incidence of many cancers between different populations. A diet rich in fat has been linked to the risk of hormone-dependent cancers such as prostate and breast cancer. A study pointed out that saturated fat consumption was significantly associated with prostate cancer survival, those in the upper tercile being at three times the risk of dying from prostate cancer (HR 3.13, 95% CI 1.28–7.67) compared with men in the lower tercile. Therefore, moderate reduction of saturated fat, to less than 10%, may reduce the risk of dying from prostate cancer (131). This dietary goal has been recommended to promote health and primary prevention of heart disease and cancer. Men who consumed 5% more calories per day from saturated fats and 5% less calories per day from carbohydrates after diagnosis had a 2.8-fold increase in prostate cancer–specific mortality (HR 2.78, 95% CI 1.01–7.64), while men who consumed 10% more daily calories from vegetable fats and 10% fewer calories from carbohydrates had a 33% reduction in all-cause mortality (HR 0.67, 95% CI 0.47–0.96; ref. 132). The potential mechanisms of HFD-induced prostate cancer include inflammation, growth factor signal transduction, lipid metabolism, gut microbiota, hormone regulation, and others. The prostate cancer incidence rate of Japan ranked to the third worldwide, however, the prostate cancer mortality rate of Japan ranked to the seventh worldwide. The disparity between the prostate cancer incidence and mortality rate in Japan may be due to the low intake of red meat, especially saturated fat, increased consumption of plant-based foods like soy, fish (especially n-3 polyunsaturated fatty acids), and non–sugar-sweetened drinks like green tea. Obesity was reported to be positively correlated with prostate cancer mortality (HR 1.78, 95% CI 1.04–3.04), regardless of race (133). Moreover, men with BMI ≥ 30 kg/m² had an increased risk of developing prostate cancer compared with men with BMI <25 kg/m² (OR 1.86, 95% CI 1.11–3.13). Elevated waist circumference (OR 1.76, 95% CI 1.24–2.51) and waist-hip ratio (OR 1.46, 95% CI 0.99–2.16) were also associated with increased prostate cancer risk (134).

Cigarette smoking is an important risk factor for prostate cancer. Individuals that began smoking before diagnosis (HR 1.50, 95% CI 1.06–2.13) or after diagnosis (HR 1.71, 95% CI 1.09–2.67) were at higher risk of prostate cancer–related mortality compared with never smokers. Additionally, prostate cancer survivors that quit smoking less than 20 years before diagnosis were at dramatic higher risk of prostate cancer–related mortality (HR 1.29, 95% CI 1.04–1.61; ref. 135). The 10-year incidence of prostate cancer–related mortality was 4.5%, 4.8%, and 5.2% for never, past, and current smokers, respectively (136). Men who engaged in high [more than 47.3 metabolic equivalent task (MET-hours/week)] and medium (15.8 - 47.3 MET-hours/week) physical activity levels were found to have reduced prostate cancer risk in Vietnam, with the adjusted OR being 0.27 (95% CI 0.14–0.49) and 0.52 (95% CI 0.35–0.77), respectively (137). However, further investigation is needed to clarify the correlation between physical activity, prostate cancer incidence, and prostate cancer mortality. In recent years, evidence linking alcohol consumption with prostate cancer risk has gradually accumulated. It was reported that low (2 drinks or 1.30–24 g/day, RR 1.08), medium (up to 4 drinks or 25–44 g/day, RR 1.07), high (up to 6 drinks or 25–64 g/day, RR 1.14), and higher (6 drinks or ≥65 g/day, RR 1.18) alcohol consumption were associated with increased prostate cancer risk (138). Furthermore, men who began consuming alcohol (≥ 7 drinks/week) earlier in life (at the age of 15–19, 20–29, 30–39, and 40–49) were shown to be at increased risk for high-grade prostate cancer diagnosis (OR 3.21) compared with nondrinkers (139). Approximately 20% of patients with prostate cancer have family history of prostate cancer. Frequently altered genes in familial prostate cancer include hereditary prostate cancer 1 (HPC1), HPC2/ELAC2, macrophage scavenger receptor 1 (MSR1), and BRCA1/BRCA2. Diseases such as diabetes (insulin and insulin-like growth factor), prostatitis, and STD, mainly HPV16 and herpes simplex virus infection, are contributing risk factors for prostate cancer. Low fat diet, smoking cession, exercise, and limited alcohol consumption are the most effective prevention methods for prostate cancer (Fig. 1).

Breast cancer had the highest incidence rate (2,261 419 new cases) worldwide in 2020, and the breast cancer mortality rate (684,996 deaths) was ranked fifth. Breast cancer is one of major global health burdens—China (18.4%), the United States (11.2%), and India (7.9%) had higher incidence rates. Breast cancer represented 18% of all cancers in women worldwide in 1980 and gradually increased to 24.5% in 2020. Breast cancer is the most common cancer affecting women, one in 20 of the world's population impacted. One in 8 in high-income countries is affected, and women are 100 times more likely to develop breast cancer than men. The breast cancer incidence rate has gradually increased in young women less than 40 years and currently stands between 10% and 15%. The risk factors of breast cancer are complex and varied, mainly including excess BMI, alcohol consumption, physical inactivity, diets, smoking, hormonal factors (menstrual, reproductive, usage of hormone medication), stress, and family history (Fig. 1; Supplementary Table S1). In 2014, more than 1.9 billion adults worldwide were classified as overweight, and roughly 600 million of them were classified as obese. Obesity was correlated with increased risk of breast cancer recurrence and death by 40% in estrogen receptor–positive (ER⁺) breast cancer (140). Around 23.6% of breast cancer cases were attributable to excess BMI in 2012. In a meta-analysis, it was estimated that the risk of breast cancer was elevated by 12% for each 5 kg/m² increase in BMI (141). A study including over 6 million Korean women reported that the risk of invasive breast cancer increased linearly in postmenopausal women with BMI 23 to 25 kg/m² (HR 1.11, 95% CI 1.08–1.14), BMI 25–30 kg/m² (HR 1.28, 95% CI 1.25–1.32), and BMI ≥ 30 kg/m² (HR 1.54, 95% CI 1.47–1.62) compared with women with a BMI of 18.5–23 kg/m²; significantly lower rates were observed in patients with BMI < 18.5 kg/m² (HR 0.82, 95% CI 0.75–0.89; ref. 142). Conversely, breast cancer risk decreased slightly in premenopausal women with a BMI 25–30 kg/m² (HR 0.95, 95% CI 0.91–0.98) and BMI more than 30 kg/m² (HR 0.90, 95% CI 0.82–0.98) compared with those with a BMI of 18.5–23 kg/m² (142). Another study reported the waist size and waist–hip ratio (WHR) were the major risk factors for breast cancer in Indian women, suggesting that the excess BMI was a major factor for breast cancer in this area (143). Conversely, it was reported that underweight was associated with decreased breast cancer risk (OR 0.66, 95% CI 0.49–0.88; ref. 144). Weight loss was also reported to reduce breast cancer incidence risk (OR 0.82, 95% CI 0.67–0.97; ref. 145). Interestingly, birth weights in the highest quartile (≥3,730 g) were associated with 40% higher breast cancer risk (OR 1.4, 95% CI 1.1–1.9) compared with those in the lowest quartile (<3,090 g) in Norway (146). Furthermore, each 500 g birth weight increase in premenopausal and all ages women was associated with increased breast cancer risk by 9% (RR 1.09, 95% CI 1.04–1.15) and 2% (RR 1.02, 95% CI 1.01–1.03), more significant risk was observed in women whose birth weight exceeded 3,500 g (147). The aforementioned results are controversial and highlight additional need for large-scale cohort study and detailed biologic mechanism study.

Alcohol consumption (≥30 g/d) was positively associated with breast cancer risk regardless of the ER status (ER⁺: RR 1.35, 95% CI 1.23–1.48; ER⁻: RR 1.28, 95% CI 1.10–1.49) compared with nondrinkers (148). Moreover, the breast cancer risk increased by 10.5% (RR 1.10, 95% CI 1.08–1.13) and 8.9% (RR 1.08, 95% CI 1.04–1.14) in total alcohol and wine consumption with 10 g per day in ER⁺ breast cancer. Additionally, the risk increased by 11.1% (RR 1.11, 95% CI 1.09–1.13) for every 10 g of total alcohol consumed by postmenopausal women (149). Even low alcohol consumption (5.0–9.9 g/d, or 3–6 drinks/week) could increase breast cancer risk (RR 1.15, 95% CI 1.06–1.24; ref. 150). Furthermore, there appears to be a greater correlation between alcohol consumption and breast cancer in Europe than in Asia or North America. Women who performed at least 150 minutes of vigorous exercise per week would reduce their lifetime breast cancer risk by 9%, and women who never used hormone replacement therapy could reduce breast cancer risk up to two fold (151). In addition, physical activity decreased breast cancer risk by 49% (95% CI 0.29–0.92) among postmenopausal women (152). Smoking is associated with increased breast cancer risk (HR 1.14, 95% CI 1.03–1.25), especially among women who began smoking during adolescent (HR 1.24, 95% CI 1.08–1.43) or perimenarcheal ages (HR 1.23, 95% CI 1.07–1.41). A greater relative breast cancer risk (HR 1.35, 95% CI 1.12–1.62) was also observed in women with family history of breast cancer compared with never smokers (153). Furthermore, women who smoked more than 5 years before their first live birth were reported at a 31% higher breast cancer risk than women who had never smoked (95% CI 1.14–1.51). Additionally, the higher risk was observed in 66% of Native Hawaiians, followed by 51% of African Americans, 42% of Whites, and among them, 37% for ER⁺ breast cancer and 33% for progesterone receptor–positive (PR⁺) breast cancer (154). Saturated fat, red and processed meats were found to be positively correlated with breast cancer risk, while vegetable intake provided protective effects against breast cancer. Early menarche (generally less than 12 years old), late menopause (older than 55 years old), unmarried, childless, late childbearing, no breastfeeding, exposure of the chest to high dose of radiation, long-term use of external estrogen, family history, and mammographic density are other contributing risk factors for breast cancer. In addition, a large percentage of breast cancer patients reported feelings of depression (38.2%) and anxiety (32.2%), indicating that stress may be closely correlated with breast cancer development (155, 156). Prolonged stress leads to disturbances in the hypothalamic-pituitary-adrenal axis and suppresses important facets of the immune response (157). It is foreseeable that stress plays an important role and may act as a key risk factor in cancer progression. However, additional studies are needed to identify the stress-associated molecular mechanisms that contribute to cancer progression. It is believed that approximately 50% of breast cancer can be prevented by chemoprevention (raloxifene, tamoxifen, exemestane, and anastrozole), energy restriction/weight control, healthy diets (control of red meat, increased intake of fish, vegetables, fruits, soy, and sodium), physical activity (150 minutes of moderate–intensity physical activity per week), and limited alcohol consumption (Fig. 1).

There were an estimated 604,127 new cervix uteri cancer cases and 341,831 cervix uteri cancer–related deaths worldwide in 2020. Links between HPVs and cervical cancer were first suspected nearly 50 years ago. HPV is a double-stranded DNA virus that belongs to the papovaviridae family. Between 1974 and 1976, scientists led by Zul Hausen began to hypothesize and explore the link between HPV and cervical cancer (158–160). In 1976, Messels and Fortin published two reports outlining the presence of papillomavirus within a cervical smear (161). HPV 16 and HPV 18 were the first HPV types isolated directly from cervical cancer biopsies. Subsequent advances within molecular biology enabled their cloning in 1983 and 1984, respectively, thereby resulting in a rapid expansion of the field (162, 163). Research conducted in the 1980s and 1990s, confirmed that HPV infection can induce a variety of malignant tumors, including cervical cancer. Around 200 sexually transmittable HPV types were identified and classified into 2 groups based on the carcinogenic properties: high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, and 82) and low-risk HPV types (6, 11, 40, 42, 43, 44, 45, 54, 61, 72, and 81; ref. 164). Ninety percent of low-risk HPV infections disappear or enter dormancy within 12 to 24 months, while high-risk HPV infection can be persistent and increase cervical cancer risk (165). It was reported that 99.7% of cervical cancer specimens were infected with a high-risk HPV variant. HPV 16 and 18 alone were detected in 70% of invasive cervical cancer and high-grade squamous intraepithelial lesions (166). Geographically, the higher HPV prevalence rates were observed in sub-Saharan Africa (24%), Eastern Europe (21.4%), and Latin America (16.1%); the lower rates were observed in North America (4.7%) and Western Asia (1.7%; ref. 167). HPV 16 was the most common HPV virus worldwide, with prevalence rates accounting for 32.3% of all infections in Southern Asia, 28.9% in Southern Europe, 24.4% in Western Europe, 24.3% in Northern America, and 12% in Africa (167). HPV 16 was predominantly detected in squamous cell carcinomas (SCC), ranging from 46% of SCCs in Asia to 63% of SCCs in North America. HPV 18 was detected in 10% to 14% of SCC specimens and 37% to 41% of adenocarcinomas. The combination of HPV 16 and HPV 18 was detected in 74% to 77% of SCCs in Europe and North America, and 65% to 70% of SCCs in Africa and Asia (168). HPV prevalence was highest in women younger than 35 years old, decreasing in women of older age. However, the obvious second peak of HPV prevalence was observed in women aged 45 years or older in Africa, America, and Europe. In Japan, the cervical cancer incidence rate increased between 20 to 30 years and peaked at 40 to 50 years in 1999 to 2013. In 1995, HPV 16 and HPV 18 were defined as causative agents for cervical cancer by the IARC. That same year, the preventive large-scale papillomavirus vaccination in dogs and rabbits was detected (169, 170). In 2001, the immunogenicity of papillomavirus-like particle vaccines in human was reported (171). HPV vaccines utilization has significantly decreased the incidence of cervical cancer in many countries all over the world. On November 17, 2020, the WHO released the Global Strategy to Accelerate the Elimination of Cervical Cancer (GSAECC). The initiative outlines three key measures: vaccination, screening, and treatment, which are expected to reduce new cases and 5 million cervical cancer–related deaths by more than 40% by 2050. The launch of the GSAECC as defined by the WHO is a historic milestone, marking the first time that 194 countries around the world have committed to eliminating a cancer in accordance with a resolution adopted by the World Health Assembly.

Aside from HPV infection, other risk factors for cervical cancer include HIV infection, smoking, ethnicity, sexual life, oral contraceptive intake, and obesity (Fig. 1; Supplementary Table S1). It was reported that HPV infection was detected at higher rates in women who were HIV-positive than in those who were HIV-negative, that is, cervical cancer incidence was positively associated with HIV infection (172). The most affected regions were geographically located in Africa, with 63.8% of women with HIV-positive cervical cancer living in Southern Africa and 27.4% of women who were HIV-positive living in Eastern Africa (173). Cervical cancer ranks third of all cancer cases attributed to smoking among females depending on smoking history and daily cigarette smoking. With respect to race, black women were shown to be at higher risk for developing advanced-stage cervical cancer than white women regardless of age, insurance status, and geography (174). However, the racial disparity is disappearing. The age at the first sexual encounter, number of sexual partners, and unhealthy sexual life are important risk factors for cervical cancer. Obesity was reported to weakly correlate with increased risk of cervical cancer, which needs more evidence; however, additional research is needed to further assess its association with cervical cancer risk.

Skin cancer is mainly classified into three types, basal cell carcinoma (BCC), SCC, and melanoma. BCC of the skin is thought to be more common and disfiguring than any other skin cancers, but it is usually treatable. SCC of the skin is less common than BCC, but in rare cases it can lead to death. Melanoma is the most common skin cancer in morbidity and mortality according to data systematically gathered in the United States. In 2020, there were an estimated 324,635 new cases of melanoma and 57,043 melanoma-related deaths worldwide. Melanoma was first described as a distinct oncologic entity in Europe and North America in 1804 and 1837, respectively (175). Melanoma was considered a rare cancer in the early 20th century, however, melanoma incidence rates began to increase in the 1930s, and the number of deaths elevated sharply between 1950 and 1980. At the beginning of the 20th century, 80% to 90% of children in Northern Europe and the United States were vitamin D deficient (176). The medical community began to recognize the role of sunlight in treating diseases such as rickets and tuberculosis, and sunlight therapy had become the standard treatment for rickets by 1919. However, the link between sunlight and melanoma was first discovered in 1965 by Henry Lancaster (177). Research performed in the 1960s gradually hinted at an association between UV rays exposure and skin cancer. Subsequent experiments using in vitro and in vivo model systems later confirmed a causative link. It is estimated that UV radiation causes nearly 70% of melanomas and 90% of nonmelanoma skin cancers, suggesting that development of such tumors may be preventable (178). Skin cancer is a rapidly growing epidemic in the United States, with more than three million five hundred thousand new cases diagnosed each year, and the rates of skin cancer have tripled since the 1970s (179). In 2014, the Surgeon General's Call to Action to Prevent Skin Cancer made recommendations about the growing prevalence of skin cancer in the United States and identified ways to reduce the risk of developing skin cancer through primary prevention and education. In 1988, Australia became the first country to launch a skin cancer prevention program, called SunSmart, which aimed to reduce the incidence, morbidity, and mortality of skin cancer by informing the public of the dangers of UV radiation. It was estimated that the campaign prevented nearly 50,000 skin cancer cases and 1,400 skin cancer–related deaths between 1988 and 2011 (180). Moreover, despite ozone layer depletion over Australia, the incidence of cutaneous melanoma in Australia has stabilized and the incidence of invasive melanoma is declining in Australians less than 55 years old (181). Among all WHO continents, Europe (46.4%) and North America (32.4%) had the highest melanoma incidence rates, accounting for 78.8% of all new cases. Europe (46.2%) and Asia (21%) had the highest mortality rate, accounting for 67.2% of melanoma-related deaths worldwide. Since the 1960s, melanoma has become one of the most frequent cancers in fair-skinned populations. The most common risk factor for melanoma is UV exposure. UV light stimulates melanocytes to produce melanin, which appears as tanned skin, indicating damage to the skin, skin cells, as well as DNA, and stricter exposure can lead to sunburn (182). The degree of skin damage induced by UV exposure varies depending UV radiation types, UV exposure patterns, variations in UV by time and place, and occupational UV exposure. Undoubtedly, UVA (315–400 nm) and UVB (280–315 nm) radiation from the sun are the main types of UV radiation (UVA, UVB, and UVC) responsible for inducing skin damage, because UVC was blocked by ozone layer and may not reach the surface of earth (183–185). Each skin cancer type is associated with different UV radiation exposure patterns. BCC and SCC are commonly associated with chronic cumulative exposure, including occupational outdoor exposure, while melanoma is widely associated with intermittent exposure and sunburn history. UV radiation varies greatly across the seasons, latitude, and altitude. People who live near the equator or at higher altitudes are thought to be at greater risk of melanoma (186). Occupational exposure to UV radiation can potentially increase skin cancer risk among outdoor workers, although a general consensus has not been reached. Studies have shown that outdoor workers were at increased risk for developing BCC and SCC (187). In recent years, a large number of contributions have been made to the elucidation of specific signal transduction pathways involved in UV-induced skin carcinogenesis, with most evidence indicating that the cellular signal response is UV wavelength–dependent, including the MAPK signaling cascades, EGFR signaling pathway, PI3K cascades, protein kinase C (epsilon) signal transduction, and proto-oncogene tyrosine-protein kinase Src (Src) signaling pathway (188). Progress in understanding the mechanisms of UV-induced signal transduction could lead to identifying specific targets that may aid in the prevention and control of skin cancer.

Immunodeficiency is another critical risk factor for skin cancer (Fig. 1; Supplementary Table S1). Studies have identified that immunosuppressed patients have a significantly increased risk of developing cutaneous malignancies. Additionally, neoplasms seem to grow more rapidly and are more invasive in patients with acquired immune deficiency syndrome (AIDS) than in other groups of patients (189). Skin cancer morbidity and mortality rates are higher in patients who are HIV positive than those patients in the general population (190). Moreover, cutaneous HPVs that belong to the beta genus may act as a cocarcinogen with UV radiation. This phenomenon was first reported in patients with epidermodysplasia verruciformis (EV), in which sun-exposed areas frequently developed into SCC. Mechanistically, beta HPVs promote cellular proliferation and allow cells to circumvent apoptosis that would normally occur upon exposure to UV radiation. In this manner, genetic lesions gradually accumulate and the cells become highly susceptible to malignant transformation (191, 192). Further investigation is needed to assess whether the HPV vaccine can prevent skin cancer. People with fair skin, light colored eyes, blond or red hair, dysplastic or common moles, skin burns, freckles, or having a history of sunburn may be at greater risk of developing skin cancer (193). Moreover, patients with a family history of skin cancer (melanoma, BCC, and SCC) have an increased skin cancer risk; the risk of having a second melanoma within 1 year after initial diagnosis was reported to be about 2% and about 1% for patients who have a second melanoma each year for 2 to 15 years after initial diagnosis (194). In addition, the risk of having a second case of BCC or SCC in individuals with BCC or SCC family history was 44% and 18% within 3 years, respectively, both had a 10-fold increase in the incidence compared with the general populations (195).

Arsenic is widely present in nature, and humans are exposed to arsenic through air, water, beverages, and food. Once ingested, an estimated 70% to 90% of inorganic arsenic is absorbed by the gastrointestinal tract and widely distributed through the blood to different organs, including liver, kidney, lung, bladder, muscle, and nerve (196). Arsenic has been designated as a group 1 human carcinogen by the IARC and has been causally linked to urinary bladder cancer, lung cancer, liver cancer, and skin cancer in humans (197). Interestingly, arsenic has also been used as an effective chemotherapeutic agent in the treatment of certain human cancers. Studies have found that exposure to low concentrations of arsenic induces cell transformation, whereas higher concentrations of arsenic induce cell apoptosis (198). In particular, one study reported a link between arsenic-contaminated water and skin cancer in the U.S. population, with the possibility of skin cancer occurring at arsenic concentrations less than 10 μg/L in some cases, and 10 μg/L was settled as the maximum concentration of municipal water allowed by the U.S. Environmental Protection Agency in 2001 (199). Around 300 million people worldwide are affected by arsenic contamination of groundwater. Currently, India is ranked highest in terms of arsenic poisoning due to groundwater contamination, making one in 100 people highly susceptible to the disease. A recent study indicated increased arsenic concentration in the blood in 2,000 patients with cancer, providing evidence of a link between arsenic and cancer. Blood arsenic levels were found to be higher in patients with carcinoma as compared with sarcomas, lymphomas, and leukemia. Another study reported that a total of 464 participants in China had arsenic-related skin injuries and that chronic arsenic exposure can impair residents' skin-related quality of life, sleep quality, and mental health (200). Itching and hair arsenic are independent risk factors for impaired skin health–related quality of life. However, further investigation is warranted as there are very few epidemiologic studies focused on the association between low to moderate arsenic exposure and cancer.

EBV, considered the first tumor-promoting virus, was discovered in Burkitt lymphoma cells in 1964 and has been implicated causing approximately 1% of all cancers. EBV associated with a wide range of tumors of both lymphoid and epithelial origin, mainly including Burkitt lymphoma, Hodgkin lymphoma, gastric cancer, and nasopharynx cancer. EBV is the most common and persistent viral infection in humans, with approximately 95% of the world's population remaining asymptomatic for life (201, 202). There were an estimated 133,354 new nasopharynx cancer cases and 80,008 nasopharynx cancer–related deaths in 2020. Asia has the highest nasopharynx cancer morbidity (85.2%) and mortality (85.5%) rates among all continents worldwide. Within Asia, China (46.8% new cases; 43.5% deaths) and Indonesia (15% new cases; 16.7% deaths) are the countries most affected by nasopharynx cancer. Nasopharynx cancer was once considered endemic in the southern part of China (Guangdong and Hong Kong) in the early 20th century and was dubbed ‘Guangdong cancer.’ Data from many studies have provided concrete evidence implicating EBV as a primary etiological agent for nasopharynx cancer, specifically the endemic nonkeratinizing type (203). EBV accounts for more than 85% of nasopharynx cancer cases globally, and inhibition of EBV reactivation is currently being investigated as a possible approach to prevent nasopharynx cancer relapse. EBV is associated with multiple cancers through the expression of viral oncogenic proteins and chronic inflammation (204). One study reported that intronic EBV integration could decrease the expression of the inflammation-related genes, such as TNF alpha-induced protein 3 (TNFAIP3), E3 ubiquitin-protein ligase parkin (PARK2), and cyclin-dependent kinase 15 (CDK15) in nasopharynx tumors, which may provide additional mechanistic insights into EBV-associated cancer development (205).

Several interacting factors are responsible for the onset of nasopharynx cancer. Aside from EBV infection, other risk factors include HPV infection, diet, genetic susceptibility, and smoking (Fig. 1; Supplementary Table S1). HPV infection is associated with the nonendemic, keratinizing type of nasopharynx cancer, and studies have revealed that HPV-positive nasopharynx cancer is associated with poorer outcome compared to EBV-negative nasopharynx cancer (206). Various studies have previously reported that a history of salted fish consumption has the strongest association with nasopharynx cancer, previously (207, 208). However, a more recent study showed that consumption of salted fish and preserved food stuffs were weakly associated with nasopharynx cancer in adults from southern China (209). It was reported that as compared with nondrinkers, high-frequency drinking (≥7 times/week) increased the nasopharynx cancer probability, while low-frequency drinking (<7 times/week) decreased the probability, as did a shorter duration of drinking (<20 years; ref. 210). However, one recent study reported there was no significant association between alcohol consumption and nasopharynx cancer risk, while tea drinking and milk consumption may moderately reduce nasopharynx cancer risk (211–213). Smoking was associated with higher nasopharynx cancer mortality identified by several studies.

Oral cancer is one of the most common (more than 90%) head and neck cancers, which develops within the oral cavity. There were estimated 377,713 new oral cancer cases and 177,757 oral cancer–related deaths worldwide in 2020. India (36% of new cases; 42% of deaths) and China (8% of new cases; 8% of deaths) rank highest in terms of oral cancer incidence and mortality rates among all countries. The risk factors for oral cancer include betel nut chewing, smoking, HPV infection, and alcohol consumption (Fig. 1; Supplementary Table S1). Betel nut chewing is the main risk factor for oral cancer in subcontinental countries. The betel nut, whose main carcinogenic compound is arecolin, has been classified as the group I carcinogen, and its use has been associated with oral and oropharyngeal cancer, oral lesions, oral leukoplakia, submucous fibrosis, gum disease, and cancer of the pharynx and esophagus (IARC, 2004; ref. 214). In Australia, smoking and excessive alcohol consumption (>5 standard drinks per day) are considered to be major risk factors for the development of oral squamous cell carcinoma; the relative risk was 7-fold for smoking and 6-fold for drinking more than 50 g alcohol/day (215, 216). It was reported that a population-based oral cancer screening program targeting more than 2 million cigarette smokers and/or betel quid chewers reduced stage III or IV oral cancer incidence and mortality in Taiwan (217). In addition, HPV (mainly HPV 16 and HPV 18) infection has been regarded as a risk factor for oral cancer. It was reported that HPV was detected in around 40% of 1,497 oral cancer samples from 1995 to 2015 and that its presence served as a predictor for increased risk (OR 2.82) and poor recurrence-free and overall survival of oral cancer (218, 219). However, another study showed that the frequency of HPV infection in oral cavity SCC was less than 4% and was not dramatically associated with clinical tumor features and risk factors in the Brazilian population (220). The association of HPV infection with oral cancer remains to be established via epidemiologic and detailed molecular mechanism studies.

There were an estimated 604,100 new esophageal cancer cases and 544,076 esophageal cancer–related deaths worldwide in 2020, with nearly 80% of incidence and mortality rates occurring in Asia. China has the highest esophageal cancer incidence and mortality rates, accounting for 53.7% and 55% of esophageal cancer cases and related deaths, respectively. Esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal cancer cases, over half of which occur in China, while the incidence rates of esophageal adenocarcinoma (EAC) in some developed countries is even higher than that of the ESCC. The high incidence region of esophageal cancer, comprised of nearly 90% of ESCC cases, is often referred to as the “esophageal cancer belt” in Asia, which stretches from northern Iran to Mongolia and North-Central China (221). This extension of the “Asian Esophageal Cancer Belt” coincides with the ancient Silk Road, which was established by China about 2,000 years ago (222). ESCC has major influence in the eastern “North-South Corridor,” which extends from Ethiopia and Kenya to South Africa in the African region (223). Esophageal cancer has been present in this corridor for more than half a century, dating back to 1969 (224, 225). The confirmed ESCC hotspots are clearly defined and include Linxian, China; Golestan province in Iran; Western Kenya and Southern to Malawi; the Eastern Cape province of South Africa; Calvados in France; Southern Brazil; and Uruguay (226). There are many causes of ESCC, which may vary across regions. Pickled vegetables were convincingly associated with ESCC decades ago in Linxian and other Taihang Mountain Grand Junction areas of the Henan, Hebei, and Shanxi provinces in China. The World Cancer Research Fund separately evaluated the risk factors of esophageal cancer subtypes for the first time in 2016, including “convincing” evidence of tobacco use and alcoholic beverage intake, “probable” evidence of Maté (an herbal infusion consumed in parts of South America) consumption, and “limited-suggestive” evidence of processed meat intake. There is also “limited-suggestive” evidence of the protective effects of physical activity, and fresh vegetables and fruits intake (227). There is currently “limited-no conclusive” evidence for other potential risk factors, indicating that additional investigation is required. Habitual alcohol consumption and smoking are the most important risk factors for ESCC and have been associated with more than 90% of all ESCC cases in Japan (228). Several studies have reported that consumption of hot beverages, in conjunction with alcohol consumption, could increase esophageal cancer risk in China, Iran, and Japan (229–231). Recently, one group reported a sustained increase of about 90% in ESCC risk for drinking 700 mL/day at higher temperatures (over 60°C) compared with those who drank less than 700 mL tea per day below 60°C. The IARC has concluded that the carcinogenicity associated with hot beverage consumption in humans is limited and classified “drinking very hot beverages above 65°C” as “possibly carcinogenic” (group 2A carcinogens according to the study's classification system of IARC), rather than “carcinogenic” in humans (group 1; ref. 232). The potential mechanisms of drinking hot beverages leading to ESCC may include promoted inflammatory processes and exposure to intracranial carcinogens by thermal injury, appearing after reaching threshold temperatures, with direct effects on DNA bases and/or increase the formation of carcinogenic N-nitroso compounds, PAHs, and impairment of esophageal mucosal barrier function. Moldy food and pickled vegetables were shown to contain carcinogens, mainly the nitrosamines and their precursors. Urinary exposure of N-nitrosamines was found to be dramatically higher in patients with reflux esophagitis, basal cell hyperplasia (BCH), dysplasia, and ESCC compared with normal controls in a high incidence area of China (233–235). However, additional systematic research, which takes into account dose–response relationships and reference ranges, is needed to assess the contribution of nitrosamine exposure to ESCC. We hypothesize that thermal injury is the switch of ESCC carcinogenesis and that alcohol consumption and smoking are the dynamic system for esophageal cancer progression (Fig. 1; Supplementary Table S1). It was reported that HPV infection was detected in 56.1% (244 of 435 samples) of esophageal carcinoma cases independent of region and ethnic group of origin, indicating that HPV infection may be involved in esophageal carcinogenesis (236). An additional study reported that the HPV infection rate was high in patients with esophageal cancer in Shenqiu County, Henan, China (237). However, some studies have suggested that HPV infection is not clearly associated with esophageal cancer or the prognosis of esophageal cancer (238–240). Other risk factors including poor diet, oral health conditions, betel quid chewing, and microbiome dysregulation may increase esophageal cancer risk; however, much of the evidence supporting their contribution to esophageal cancer development is currently inconclusive.

Based on the “1 + X” etiology principle, we propose the cancer prevention strategy: eliminate “1,” and prevent “X.” Based upon this strategy, it is estimated that 30% to 50% of cancers may be preventable provided that necessary measures were taken. Lack of information on cancer etiology with an unclear/wrong “1” or no action for eliminating/preventing the “1” would contribute to failed or marginal trials. For example, the ban on smoking significantly reduced lung cancer incidence rate in the United States, and the eradication of H.pylori dramatically decreased gastric cancer incidence rate in Japan, while no compulsory measures to ban smoking and eradicate H.pylori in many countries like China, South Korea, and India are the reasons for the high incidence of lung, gastric, and other cancers in these countries. And no definite “1” for esophageal cancer in the past caused still high incidence and mortality rate of esophageal cancer in China. Primary prevention is used and is supposed to stop preneoplasia or benign tumors when exposed under average or intermediate cancer risks. Secondary prevention is applied when exposed average or high cancer risks. Tertiary prevention is employed when preneoplasia, benign, or malignant tumors occur, however, it may not stop the tumor development under these conditions (Supplementary Fig. S1A). Cancer etiology and prevention began in antiquity, as early as 168 B.C., when the positive correlation between unhealthy diet and cancer was found by Galen, the Roman physician. So far, numerous groundbreaking researches have confirmed that cancer prevention relies on cancer etiology (Supplementary Table S2; refs. 241, 242). Specially, no smoking for lung cancer and pancreatic cancer, H.pylori eradication and anti-EBV infection for gastric cancer, HBV vaccination and anti-HCV infection for liver cancer, weight control for colorectal and breast cancer, low-fat diet for prostate cancer, HPV vaccination and anti-HIV infection for cervical cancer, avoid UV radiation for skin cancer, anti-EBV infection for nasopharynx cancer, no betel nut chewing for oral cancer, and avoid thermal injury (hot beverages) for esophageal cancer. It has been well established that from tumor cell initiation to cancer formation will take many years, and the “X” also plays important roles in the tumor initiation and progression. This will provide an important window of opportunity for cancer prevention and control. For example, around 30% to 40% of all instances of cancer could be prevented simply by preventing the “X” with modification of diet, maintenance of optimum body weight, and regular physical activity (Supplementary Fig. S1A). Modification of diet alone by increasing vegetables and fruits intake could prevent 20% or more of all cases of cancer and may potentially prevent approximately 200,000 cancer-related deaths annually. The common and effective preventive strategies for most cancers are to avoid infections (H.pylori, HBV, HCV, HPV, EBV, HIV, Opisthorchis viverrini, Clonorchis sinensis, and Schistosoma haematobium), no smoking (include second smoke or tobacco products), limited alcohol consumption, diet with abundant fresh fruits and vegetables, be physically active (control weight), be optimistic and peaceful, as well as conduct early detection when people reach old age and/or have a family history (Supplementary Fig. S1B). The 2016 U.S. cancer screening guidelines recommend annual colonoscopy for people more than 50 years old, and the screened rate rose from 21% in 2000 to 60% in 2015. As a result, the incidence of colorectal cancer has declined steadily at a rate of 3% a year for nearly 40 years, from 1975 to 2013 (243). However, only when the prevention strategy and early detection rises by the influence of the government and all populations, can it get enough attention and the ideal effect, which need international cooperation.

The battle against cancer has yielded fruitful results, due to the results of etiologic studies, early detection, effective prevention, drug discovery, and therapeutic strategies. Progress in eliminating the cancer burden has not been smooth, steady, or uncontroversial. Regrettably, efforts to liberate mankind from this scourge remain incomplete. However, there are grounds for optimism regarding the future, as our understanding of cancer continues to rapidly advance. Although the detailed molecular mechanisms governing carcinogenesis and cancer progression are complex, advances in artificial intelligence, deep learning, large-scale data processing, and experimental methodologies may facilitate the identification of clinically actionable targets in the near future. Additionally, focused and more widespread application of preexisting knowledge, particularly in prevention and early detection efforts, may have a profound effect of minimizing cancer incidence and mortality. The successes of the HBV and HPV vaccines in preventing liver cancer and cervical cancer highlight a pertinent example of the importance of vaccine research in the grand scheme of public health and suggest that research into therapeutic vaccines targeting HCV, EBV, and HIV could be equally as impactful. Research in the burgeoning domains of immunotherapy, fecal microbiota transplantation, and combination therapy are to be developed for cancer treatment. However, it would undoubtedly require less resource expenditure if cancer could be nipped in the bud by preventative measures. This can be achieved through eliminating the main causes (smoking, H.pylori, EBV, HBV, HCV, HPV, HIV, Opisthorchis viverrini, Clonorchis sinensis, Schistosoma haematobium, UV, betel quid, thermal injury, excess BMI, and so on) of tumorigenesis and reducing the auxiliary risk factors (alcohol consumption, poor diets, physical inactivity, obesity) associated with cancer progression. Moreover, early detection is extremely important for older individuals or those with a family history of cancer. Cancer prevention should adopt the concept of cancer intercept, that is, to prevent transformed cells from becoming malignant cancers. Potential preventative actions contain adopting a healthy lifestyle, refraining from carcinogens, inhibiting inflammation and pathologic angiogenesis, regulating metabolism, rectifying insulin resistance, and monitoring intestinal microbiota changes. Several repurposed FDA-approved drugs have been shown to reduce cancer incidence and mortality rate. For instance, aspirin is now recommended for the prevention of colorectal cancer and other tumors. Similarly, metformin and tamoxifen may be valuable in reducing the risk of pancreatic and breast cancer, respectively. Furthermore, extensive research over the past several decades has identified numerous dietary and botanical natural compounds that have chemoprevention potential. Due to their low toxicity/safety, antioxidant properties, and general acceptance as dietary supplements, fruits, vegetables, and other dietary elements (phytochemicals and minerals) are being investigated for use in cancer prevention. Cancer is currently an alarming global health issue, however, insights gained over the past few decades suggest that many types of cancer are preventable and that the implementation of strategic measures may avert incidence rates by nearly half in the future.

No disclosures were reported.

This study was supported by National Natural Science Foundation of China (No. 82073075) and the China-US (Henan) Hormel Cancer Institute.