Background:

The epidemiology of nasopharyngeal carcinoma (NPC) has long been a source of fascination due to the malignancy's striking geographic distribution, the involvement of the oncogenic Epstein–Barr virus (EBV), the unique association with intake of Chinese-style salt-preserved fish, and etiologic heterogeneity by histologic subtype.

Methods:

This review summarizes the current epidemiologic literature on NPC, highlighting recent results from our population-based case–control study in southern China.

Results:

Findings from our case–control study provide new insight into the epidemiology of NPC, including a diminished role of Chinese-style salt-preserved fish, a profound impact of EBV genetic sequence variation, modest positive associations with passive smoking and household air pollution, and possible effects of oral health and the oral microbiome. Recent findings from other studies include a protective association with infectious mononucleosis, suggesting a causal role of early EBV infection; familial risk conferred by shared genetic variation in the host antibody-mediated immune response to EBV infection; and an unclear association with occupational exposure to formaldehyde.

Conclusions:

To shed further light on the interplay of environmental, genetic, and viral causes of NPC, large pooled studies must accumulate sufficient cases with detailed exposure data.

Impact:

New epidemiologic findings have reshaped the causal model for NPC.

For decades, nasopharyngeal carcinoma (NPC) has been endemic in indigenous populations in East and Southeast Asia, the Arctic, North Africa, and the Middle East (1). The persistence of this malignancy in certain geographic regions suggests that genetic and/or stable environmental risk factors contribute substantially to its development. The involvement of the Epstein–Barr virus (EBV) in NPC pathogenesis adds another layer of complexity to its etiology. Although our understanding of the causes and prevention of NPC remains incomplete, important epidemiologic advances have recently been made. Between 2010 and 2014, we and our colleagues in China, Sweden, and the United States conducted a large, rigorously designed population-based case–control study of NPC in Guangdong Province and Guangxi Autonomous Region in southern China (2). New and emerging results from this study and other recent investigations have helped to shed light on the genetic, environmental, and infectious causes of NPC, and how the role of some risk factors may have shifted over time.

NPC is a rare malignancy throughout most of the world, with age-standardized rates generally below 1 per 100,000 person-years. Substantially higher rates, however, have long been observed in the Cantonese population of southern China, and intermediate rates are found in indigenous populations in Southeast Asia, the Arctic region, North Africa, and the Middle East (Figs. 1 and 2; ref. 3). On the basis of Chinese cancer registry data for 2008–2012, age-standardized incidence rates of NPC varied by up to 50-fold, from 0.5 per 100,000 among males in northern China to 25 per 100,000 among males in southern China (Fig. 3; ref. 4). In 2018, an estimated 129,079 incident cases of nasopharyngeal cancer were diagnosed internationally (85% in Asia) and an estimated 72,987 deaths occurred from nasopharyngeal cancer, making it the 23rd most common incident cancer in the world and the 21st most common cause of cancer death worldwide (3). In Southeast Asia, nasopharyngeal cancer ranked 9th among incident cancers and 8th among cancer deaths (3).

Figure 1.

Estimated age-standardized (to the world population standard) incidence rates of nasopharyngeal cancer among males by country, 2018. Data and map from the Global Cancer Observatory (3).

Figure 1.

Estimated age-standardized (to the world population standard) incidence rates of nasopharyngeal cancer among males by country, 2018. Data and map from the Global Cancer Observatory (3).

Close modal
Figure 2.

Estimated age-standardized (to the world population standard) incidence rates of nasopharyngeal cancer among females by country, 2018. Data and map from the Global Cancer Observatory (3).

Figure 2.

Estimated age-standardized (to the world population standard) incidence rates of nasopharyngeal cancer among females by country, 2018. Data and map from the Global Cancer Observatory (3).

Close modal
Figure 3.

Age-standardized (to the world population standard) incidence rates of nasopharyngeal cancer among men by city or county, China, 2008–2012. Data from Cancer Incidence in Five Continents, Volume XI (4).

Figure 3.

Age-standardized (to the world population standard) incidence rates of nasopharyngeal cancer among men by city or county, China, 2008–2012. Data from Cancer Incidence in Five Continents, Volume XI (4).

Close modal

NPC is classified histologically as keratinizing squamous cell carcinoma (type I); differentiated nonkeratinizing carcinoma (type II); undifferentiated nonkeratinizing carcinoma (type III); or basaloid squamous cell carcinoma, a rare subtype (5). In high-incidence areas, nearly all NPC is the undifferentiated nonkeratinizing subtype, and most of the remainder is the differentiated nonkeratinizing subtype; in low-incidence areas, a sizeable proportion of NPC is the keratinizing squamous cell subtype (6).

NPC incidence among males is double or triple that among females in most populations (Figs. 1 and 2; ref. 4). In low-risk populations, NPC incidence reaches a modest peak in young adulthood (∼ages 15–24 years), plateaus or declines slightly until ages 35–39 years, and then rises to a second, higher peak at approximately ages 65–79 years (4). In high-risk populations, in contrast, NPC incidence exhibits a single peak at approximately ages 45–59 years, followed by a plateau or a modest decline.

Within geographic regions, NPC incidence can vary substantially by race and ethnicity. In the high-risk southeastern Chinese province of Guangdong, the Cantonese-speaking population—especially the traditionally boat-dwelling Tanka ethnic group—historically had double the risk of NPC compared with other dialect groups such as the Hakka, Hokkien, and Chiu Chau (7). In Southeast Asia, NPC risk appears to be correlated with the extent of racial and social admixture with southern Chinese, particularly the ancestors of the Tanka (8). Past and recent data from Singapore show a gradient in NPC incidence by degree of intermingling with southern Chinese: rates are lowest among Indians, who have the least admixture with the Singapore Chinese population; intermediate among Malays, who have a history of intermarriage with Chinese; and highest among the Chinese (4). Consistent with the ethnic variation within China, NPC incidence remains low in Japan, where interaction with China has predominantly involved northern populations. In the United States, rates are highest among Chinese, followed by Filipinos, Blacks, Koreans, non-Hispanic Whites, Japanese, and Hispanic Whites (4).

Migration patterns and incidence trends over time also offer hints regarding the interplay of genetic and environmental risk factors in NPC development. When high- or intermediate-risk populations migrate to lower-incidence regions, their incidence of NPC declines, but remains higher than that of other races (9–12), suggesting an important role of genetic and/or early-life (perhaps viral) exposures. Conversely, risk of NPC has been shown to rise following migration of low-risk racial/ethnic groups to higher-incidence geographic areas (13, 14), indicating an etiologic contribution of environmental factors.

NPC incidence in southern China has declined steadily since the 1970s (15), in Taiwan since the 1980s (16), and in Singapore Chinese since the 1990s (17). The temporal pattern of declines in NPC incidence may be related to the relative timing of rapid economic development, which occurred first in Hong Kong, followed by Taiwan and then Singapore. In Southeast China, where industrialization has taken place more recently, NPC incidence had not decreased as of the early 21st century (18, 19). Stratification by histologic subtype of NPC reveals that the recent decline in Hong Kong was limited primarily to type I squamous cell NPC, whereas the incidence of nonkeratinizing types II and III NPC remained relatively stable (20). In the United States, although overall NPC incidence has been falling since the 1990s (21), the incidence of type II differentiated nonkeratinizing NPC has been increasing in women and men across major racial groups (22).

Infections

EBV

EBV, formally designated as human herpesvirus 4, is a ubiquitous B-lymphotropic virus that is carried latently by almost all humans. Primary infection typically occurs in childhood, when EBV usually causes no or mild symptoms (23). EBV is classified by the International Agency for Research on Cancer (IARC) as an established cause of several malignancies in humans, namely, NPC, Burkitt lymphoma, immunosuppression-related non-Hodgkin lymphoma, extranodal natural killer/T-cell lymphoma (nasal type), and Hodgkin lymphoma (24), and EBV also appears to cause a subset of gastric cancers (25). In NPC-endemic areas, cultural norms favor relatively early infection with EBV in infants and young children (26), suggesting that younger age at EBV infection may contribute to NPC development. Given the highly dissimilar international distributions of EBV, which infects nearly all people, and NPC, which is rare throughout most of the world, cofactors must mediate the effect of EBV on NPC.

Age at primary infection with EBV, for instance, appears to affect NPC risk. Two U.S. studies found that a history of infectious mononucleosis was associated with a statistically nonsignificant 60% decrease in risk of NPC (6, 27), and a registry-based study in Sweden showed that number of older siblings (an indicator of earlier age at infection with common childhood pathogens) was positively associated with NPC risk and inversely associated with infectious mononucleosis risk, supporting the early-infection model for NPC (28). However, whether infectious mononucleosis, which results from delayed primary infection with EBV in adolescence or young adulthood, is associated with NPC risk in high-incidence areas is unknown, perhaps because late infection with EBV is rare in such populations.

EBV sequence variants may influence NPC risk by modulating the virus's oncogenic potential. A 30 bp deletion and the loss of a XhoI site in EBV's oncogenic latent membrane protein 1 have been associated with an increased risk of NPC (29); otherwise, few findings have been replicated. In a large-scale whole-genome sequencing study of 270 EBV isolates from patients with EBV-associated cancer and controls, combined with a validation analysis in a separate set of NPC cases and controls from our population-based study in southern China, we identified two nonsynonymous EBV variants in the viral BALF2 gene that were strongly and highly significantly associated with an increased risk of NPC (OR = 8.69, P = 9.69 × 10−25 for SNP 162476_C, detected in 94% of cases and 65% of controls; OR = 6.14, P = 2.40 × 10−32 for SNP 163364_T, detected in 85% of cases and 46% of controls; ref. 30). In light of the high prevalence among NPC cases, the population attributable risk of NPC due to these two variants, if causal, was 83%. A phylogenetic analysis revealed that these two EBV variants most likely originated and expanded clonally in southern China. High-risk EBV variants could potentially be used as a basis for future NPC screening, for example, being assayed in saliva (31).

Genetic variation in the host immune response to EBV infection is also anticipated to affect EBV-related NPC risk. The latter hypothesis is supported by the finding of greater EBV IgA seroreactivity—a putative indicator of chronic active EBV replication—in first-degree relatives of NPC cases, especially those carrying genetic variants conferring NPC susceptibility (32), than in general community members (33–35). NPC cases, compared with controls, were also found to have a deficient CD8+ T-cell response specific to EBV nuclear antigen-1 (EBNA-1) epitopes presented by HLA class I alleles (36).

IgA antibodies against the EBV viral capsid antigen (VCA) and early antigen, as well as neutralizing antibodies against EBV-specific DNase, are abnormally elevated several years before NPC onset (37, 38). Accordingly, these antibodies have long served as the basis for large-scale NPC screening programs in high-risk populations (37, 39), although a mortality benefit has not been proven in a randomized controlled trial. Anti-EBV IgA antibodies, as well as circulating cell-free EBV DNA in plasma or serum, are also correlated with NPC tumor burden, remission, and recurrence, making them useful markers for early NPC detection and disease management (40–42). Among NPC multiplex families, but not in a general population setting, EBV-neutralizing antibodies and antibodies against the EBV glycoprotein 350, which enables EBV to enter B cells, were found to be lower in NPC cases than controls, suggesting a possible protective effect (43, 44).

Other infections

Several infectious agents other than EBV, including high-risk human papillomavirus (45, 46) and hepatitis B and C viruses (47, 48), have been studied with respect to NPC, but no causal links are established. Incidence of both type I squamous cell and nonkeratinizing types II and III NPC is approximately doubled among individuals with human immunodeficiency virus (HIV)/AIDS, as are other EBV-related malignancies (49). NPC risk appears not to be increased among immunosuppressed solid organ transplant recipients (50, 51), perhaps mirroring the higher risk of EBV-related lymphomas in HIV/AIDS than after solid organ transplantation (52), although studies in NPC-endemic regions are few.

Tobacco and other smoke

IARC classifies tobacco smoking as an established cause of NPC in humans (53). Although tobacco smoking is more strongly associated with type I squamous cell than types II and III nonkeratinizing NPC, several studies in high-incidence regions, where the vast majority of NPC is nonkeratinizing, also demonstrate a modestly increased risk of NPC associated with tobacco smoking, with two meta-analyses of more than 20 studies showing an approximately 60% greater risk among ever than never smokers (54, 55). Smoking may increase NPC risk in part through reactivation of latent EBV infection, as suggested by studies that reported positive associations between cigarette smoking and elevated levels of anti-EBV IgA antibodies among subjects without NPC (56–58).

In line with prior findings, we found in our population-based case–control study in southern China that NPC risk was significantly increased among men who currently smoked [OR = 1.34; 95% confidence interval (CI): 1.15–1.57], but not those who quit smoking at least 4 years earlier (OR = 0.92; 95% CI: 0.72–1.18), compared with never smokers (59). Risk increased with intensity, duration, and cumulative pack-years, and decreased with later age at smoking initiation. Fewer studies have evaluated secondhand smoke as a risk factor for NPC, with inconsistent but mostly positive results (53–55). We observed a 24%–30% elevation of NPC risk in association with passive smoking during childhood or spousal passive smoking during adulthood (59).

Betel nut chewing is classified by IARC as an established cause of oral and esophageal cancers in humans (53). Three case–control studies of NPC, however, found no association (60–62), whereas a positive association was reported for familial NPC after age 40 years in Taiwan (60). Smokeless tobacco use was not associated with NPC in two studies in North Africa (63, 64), one of which found a positive association with cannabis smoking (63).

IARC classifies indoor emissions from household combustion of coal as a cause of lung cancer, but whether household air pollution causes NPC is not yet clear. Epidemiologic findings are inconsistent, with up to a 5-fold excess risk of NPC associated with domestic wood fire exposure in three studies in China (65–67) and one in Nigeria (68). Case–control studies in North Africa also reported increased NPC risk in association with poor household ventilation (69) and use of a traditional compact charcoal oven for cooking in childhood, but not adulthood (63). Other studies in southern China, however, found no association of NPC risk with exposure to indoor combustion, and studies examining burning incense or antimosquito coils have also yielded mixed results (61, 67, 70–75).

In our population-based case–control study in southern China, results generally supported an adverse impact of household air pollution on NPC risk. We observed positive associations of NPC risk with use of wood, coal, or kerosene as cooking fuel (OR for wood = 1.34; 95% CI: 1.03–1.75; OR for coal = 1.70; 95% CI: 1.17–2.47; and OR for kerosene = 3.58; 95% CI: 1.75–7.36, comparing ever vs. never use); having less ventilation in the kitchen, hallway, or bedroom (OR for kitchen = 1.67; 95% CI: 1.34–2.08; OR for hallway = 1.89; 95% CI: 1.55–2.31; OR for bedroom = 3.08; 95% CI: 2.46–3.86, comparing smaller vs. larger windows); and residential exposure to cooking smoke or burning incense (OR for smoke = 1.53; 95% CI: 1.20–1.94; OR for incense = 1.59; 95% CI: 1.31–1.95, comparing highest vs. lowest category of exposure), whereas burning antimosquito coils was associated with lower NPC risk (76).

Two studies that evaluated outdoor air pollution in Taiwan reported positive associations between ambient air levels of fine or coarse particulate matter and NPC risk (77, 78), whereas a study of 10 Chinese cities found no significant association with fine and coarse particulate matter combined (79). In both settings, ambient air levels of nitrogen dioxide were associated with greater NPC risk (77, 79).

Diet

Salt-preserved fish and other foods

Dietary consumption of Chinese-style salted fish is classified by IARC as a known cause of NPC (53), and consumption of traditional Asian pickled vegetables is classified by IARC as “possibly carcinogenic to humans,” based on “limited evidence” from epidemiologic studies of NPC, stomach cancer, and esophageal cancer (80). Traditional consumption of salt-preserved foods in southern China, Southeast Asia, North Africa, the Middle East, and the Arctic may explain part of the distinctive international distribution of NPC. In past studies, the relative risk (RR) of NPC associated with weekly consumption, compared with no or rare consumption, of Chinese-style salt-preserved fish generally ranged from 1.1 to 4, and the RR for daily consumption ranged from 1.8 to 20 (53, 80). The carcinogenic mechanism of Chinese-style salt-preserved fish may be mediated through dietary exposure to certain N-nitrosamines, bacterial mutagens, direct genotoxins, and/or EBV-reactivating substances (53, 80).

Studies in NPC-endemic regions have also found positive associations, albeit less consistently, with consumption of other preserved food items, including meats, eggs, fruits, and vegetables (38, 58, 62, 69, 81–83). A meta-analysis of six studies in China, Southeast Asia, and North Africa found that relatively high versus low intake of various preserved vegetables was associated with a doubling of NPC risk (84). Preserved food consumption may also increase NPC risk in low-incidence regions, including northern China and North America (85, 86).

More recently, however, we found that in southern China in 2010–2014, consumption of Chinese-style salted fish in adulthood, including either hard salted fish (which is prepared by directly salting and then drying) or soft salted fish (which is salted and dried after initially undergoing natural decomposition), was not associated with increased NPC risk (87). Although intake of hard salted fish during adolescence and overall intake of salted fish during childhood were associated with significantly elevated risk of NPC, the strongest ORs were more modest than in prior studies, on the order of 1.19 (95% CI: 1.03–1.39) to 1.56 (95% CI: 1.24–1.97 for weekly vs. none), respectively. We also found ORs of approximately 1.2 to 1.5 in association with the highest category of consumption of salted eggs in adulthood and adolescence, and pickled vegetables at all three time periods, whereas fermented black beans or bean paste (but not bean curds) exhibited an inverse association with NPC risk. The weak associations in our study could be due in part to lower absolute intake of Chinese-style salted fish in the general population of southern China in recent years (87), leading to a narrower range of exposure and a smaller attributable risk. Residual confounding by socioeconomic status—for instance, correlations of higher socioeconomic status with greater intake of soft salted fish (which is typically more expensive than hard salted fish) and lower risk of NPC—also could have skewed our results. Nevertheless, our equivocal findings for Chinese-style salted fish and other preserved foods suggest that dietary factors may play a lesser role in NPC development than in the past.

Fresh fruits and vegetables

A protective effect of fresh fruits and/or vegetables on NPC is suggested by several case–control studies (81–83, 88–90) and a meta-analysis (84). Results are most likely confounded to some extent by other environmental factors, however, and the impact of any particular food item is difficult to identify. Potential antioxidant, anti-inflammatory, and/or anti-nitrosation effects of fruits and vegetables are suggested by inverse associations of NPC risk with dietary intake of carrots and other red/orange/yellow vegetables (81, 85, 89, 90), green leafy vegetables (65, 89), citrus fruit, oranges, or tangerines (81, 82, 86, 89, 91), vitamin E (92), vitamin C (86), and carotenoids (93).

Dietary patterns

In studies that classified dietary patterns, rather than individual food items, diets with high inflammatory potential (broadly, high in saturated fat and carbohydrates, and low in polyunsaturated fatty acids and flavonoids) were associated with greater NPC risk (94–96), as were diets high in animal products and starches (97). Conversely, adherence to a healthy diet, evaluated in accordance with international guidelines, was associated with lower NPC risk in southern China (98), while a diet rich in fruits, vegetables, milk, fresh fish, eggs, and tea was inversely associated with NPC risk in Taiwan (99). Conflicting results were observed for a traditional Mediterranean diet (98, 100).

In our own population-based case–control study, a predominantly plant-based diet in adulthood was associated with a 50% reduction in NPC risk (OR = 0.48; 95% CI: 0.38–0.59 for highest vs. lowest quartile), whereas a diet heavy in animal products was associated with a doubling of risk (OR = 2.26; 95% CI: 1.85–2.77); results were similar but attenuated for dietary patterns in adolescence (101). Although residual confounding remains possible, these findings may point to a shift away from traditional southern Chinese foods and toward more Western foods as influences on NPC risk in the modern era.

Traditional herbal medicines

Use of Asian traditional herbal medicines was associated with a 2- to 4-fold excess risk of NPC in some case–control studies (61, 65, 70, 102), but not others (72–74, 88). Two studies, including ours, found inverse associations of NPC risk with consumption of Cantonese-style slow-cooked herbal soup (83, 103), including nine specific plant species commonly used in such soups (103); however, these studies found conflicting inverse and null results, respectively, for consumption of Cantonese-style herbal teas. Associations with use of traditional herbal medicines are susceptible to confounding by indication and, in case–control studies, reverse causation. Confounding by other aspects of a traditional lifestyle, such as diet and use of solid fuels for cooking and heating, is also a concern. Nevertheless, traditional herbal plants may plausibly contribute to NPC development by promoting or inhibiting EBV reactivation, as demonstrated in vitro (104).

Alcohol and tea

The reported association between alcohol intake and NPC risk is inconsistent, with statistically null results in several studies, especially in high-incidence areas, but positive associations in other studies in high- and low-incidence populations (105, 106). Two meta-analyses found a positive meta-RR for the highest versus the lowest category of alcohol intake in combined case–control studies, with a J-shaped exposure–response curve that, if real, may contribute to the inconsistency of results across study populations with different alcohol drinking habits (105, 106). The lack of association between alcohol and NPC risk in two prospective cohort studies in Singapore (107) and Shanghai (108), however, suggests that bias may contribute to the positive findings in case–control studies. We, too, observed no apparent association between alcohol intake and NPC risk in southern China (109).

Three case–control studies found an inverse association between tea consumption and NPC risk; one study reported this result only for green tea (110), another reported inverse associations with all six specific types of tea evaluated (111), and a third did not distinguish among types of tea (58). In our study, current intake of tea, including black or pu'er and green or jasmine tea, but not oolong tea, was associated with significantly lower risk of NPC (109). The lack of a monotonic inverse exposure–response trend, however, may indicate a noncausal explanation.

Medical conditions

Oral and respiratory tract conditions

Most studies investigating prior chronic ear, nose, throat, and lower respiratory tract conditions found positive associations with NPC risk, with RRs usually around 2.0 or higher (73, 74, 112–119). This apparent association could be explained by a promoting effect of chronic inflammation in the nasopharyngeal mucosa, or perhaps by the formation of carcinogenic N-nitroso compounds from nitrites generated from nitrates by certain bacteria. Alternatively, the association between chronic respiratory tract infections and NPC risk could be explained by reverse causation or various types of bias, including recall bias. The latter interpretation is corroborated by our own study, where positive associations between NPC risk and a history of chronic ear, nose, and throat diseases and use of related medications mostly disappeared after exclusion of the 5 years prior to diagnosis or interview (120); and by a population-based registry linkage study in Taiwan, where chronic rhinosinusitis was associated with greater incidence of NPC within 1 year, but not after longer follow-up (121).

In our population-based case–control study in southern China, we found positive associations between some indicators of poor oral health and NPC risk (e.g., for having > 3 filled teeth vs. none, OR = 1.55; 95% CI: 1.13–2.12) and an inverse association with brushing teeth at least twice per day versus less (OR = 0.62; 95% CI: 0.55–0.70; ref. 122). Using rRNA sequencing, we also found significantly lower oral microbial diversity in NPC cases than controls, as well as a pair of closely related coexcluding Granulicatella adiacens sequence variants that were associated with both NPC risk and microbial community diversity (123). These findings suggest that subspecies niche specialization in the oral microbiome may affect NPC risk.

Increased NPC risk was observed in national registry-based studies of patients with diabetes mellitus (124) and women with gestational diabetes mellitus in Taiwan (125). In addition, a hospital-based case–control study in Italy reported that differentiated NPC, but not undifferentiated NPC, exhibited a significant positive association with metabolic syndrome, and nonsignificant positive associations with type 2 diabetes mellitus, hypercholesterolemia, and obesity (126). Another registry-based study in Taiwan, however, reported a significant inverse association between diabetes mellitus and NPC risk (127), and two other investigations of diabetics in Taiwan showed that treatment with metformin was associated with lower risk of subsequent NPC (128, 129).

Occupation

IARC classifies formaldehyde as an established cause of NPC and leukemia (130), and wood dust (131) as an established cause of NPC and cancer of the nasal cavity and paranasal sinuses, based on studies of occupational exposures in worker populations. The European Chemicals Agency (ECHA), in contrast, does not classify formaldehyde as a known human carcinogen (132), but rather as a substance that is “presumed to have carcinogenic potential for humans,” largely based on animal evidence.

Formaldehyde

Most occupational epidemiologic studies of formaldehyde exposure and NPC risk have been conducted in low-incidence regions, where findings may be driven by type I squamous cell carcinoma—a possibility supported by the development of squamous cell carcinomas of the nasal cavity in rodents chronically exposed to high levels of formaldehyde vapors (133, 134). Few studies have been conducted in East and Southeast Asia, with mixed null (135, 136) and positive findings (61, 137). A 2010 meta-analysis of occupational formaldehyde exposure and NPC risk found no significant adjusted association based on six case–control studies, and no association based on seven cohort studies after excluding a single plant from a U.S. study of 10 industrial plants (combined standardized mortality ratio = 0.72; 95% CI: 0.40–1.28; ref. 138). Epidemiologic studies post-dating the most recent IARC review of formaldehyde (130), including cohort studies of occupational exposure to formaldehyde in Finland (139), the United States (140), and Italy (141), as well as case–control studies in Hong Kong (136) and Finland, Sweden, Norway, and Iceland combined (142), also found no excess risk of NPC. Equivocal results were reported in a retrospective cohort study of laminated plastic workers in Italy, which did not estimate an RR for NPC (143); and our own population-based case–control study in southern China, where we found a positive association with self-reported ever occupational exposure to formaldehyde, but no trend with duration of use (144).

The pivotal epidemiologic evidence cited in support of an effect of formaldehyde on NPC comes from a retrospective cohort study of over 25,000 workers employed before 1966 at 10 U.S. plants that produced or used formaldehyde (145–147). Although initial analyses revealed an overall increase in NPC risk in this cohort, no significant overall excess of NPC mortality was observed with the most recent follow-up through 2004, nor were significant positive exposure–response trends observed when exposed workers were compared with unexposed workers as the reference group (147). Positive trends in NPC risk were seen for peak exposure, average exposure intensity, and cumulative exposure only when unexposed workers were excluded from the analysis. The positive findings, however, were driven by a single plant where six of the 11 observed NPC deaths occurred, whereas the remaining nine plants exhibited a nonsignificant deficit of NPC mortality (148, 149). An unusually small proportion of deaths coded as unspecified pharyngeal cancer at that single site suggests that diagnostic or death certificate coding bias, along with shared exposures encountered elsewhere, probably contributed to the apparent excess of NPC (150, 151). Thus, the experience at that location may be the exception rather than the rule.

Dust inhalation

Studies of NPC risk among wood workers and others with potential occupational exposure to wood dust have yielded mixed results, with positive associations in several studies, but no association in others, including ours (144). Two recent meta-analyses found statistically significant positive associations between occupational exposure to wood dust and NPC risk, but results were highly heterogeneous across studies (152, 153), raising questions of whether the apparent association depends on NPC histological subtype, type of wood dust (e.g., hardwood or softwood), or level of exposure, as well as whether misclassification with sinonasal adenocarcinoma might contribute to the observed findings.

Occupational exposure to other types of dust, especially cotton dust, have also been studied with respect to NPC risk. Three studies from China found a significant increase in NPC risk among textile workers, with positive exposure–response trends (108, 154, 155), whereas another study from southern China found a significant deficit of NPC in association with occupational exposure to cotton dust (74). Our study in the same geographic region found positive associations of NPC risk with self-reported occupational exposure to dust from textiles, metals, cement, or coal, including positive gradients in risk with longer duration of exposure, whereas we found no significant association with self-reported occupational exposure to dust from soil, leather, or chalk (144).

Inherited susceptibility

Familial aggregation of NPC has long been documented across high-, intermediate-, and low-incidence populations (156, 157). A first-degree family history of NPC has been found to confer a 4- to 20-fold increase in risk of NPC (156, 158, 159), but not other malignancies (160). In our population-based case–control study in southern China, the cumulative risk of NPC was 5.0% (95% CI: 3.6%–7.0%) for males and 1.9% (95% CI: 1.1%–1.2%) for females with an affected relative (161). Risk was highest in siblings, with a lifetime cumulative risk of 6.3% in brothers, 3.5% in sisters, 3.4% in fathers, and 2.5% in mothers of NPC cases.

A complex segregation analysis of familial NPC in southern China found that multiple genetic variants and shared environmental factors, rather than a single major susceptibility gene, most likely explain the observed pattern of inheritance (162). Consistent with this hypothesis, disparate results were reported in four familial linkage studies, which identified four different regions of the genome shared by southern Chinese family members with NPC: a locus at 6p22 that conferred an RR of 20.9 (163); a locus at 4p12–p15 with a logarithm of odds for linkage (LOD) score of 4.2 (164); a locus at 3p21.31–21.2 with an LOD score of 4.18 (165); and a locus at 5p13.1 with an LOD score of 2.1 (166). Focusing on SNPs included in standard commercial genotyping arrays, a study using genome-wide data from southern Chinese NPC cases and controls estimated that 10% of the heritability of NPC was explained by these common genetic variants (167).

Genome-wide association studies and the human leukocyte antigen region

Table 1 summarizes findings from six genome-wide association studies (GWAS) of NPC conducted in Chinese populations, each evaluating 400,000–600,000 SNPs in hundreds or thousands of subjects (168–173). Putative susceptibility loci in the human leukocyte antigen (HLA) region were identified across multiple GWAS, including SNPs in HLA-A, HLA-B, HLA-C, and HLA-DQ/DR (168, 170–172).

Table 1.

Results of genome-wide association studies of NPC.

StudyCases (n)LocusGene
Ng et al. (2009) 111 + 168 rs2212020, rs189897 Integrin-α 9 (ITGA9), 3p21 
Tse et al. (2009) 277 + 339 + 296 rs2517713, rs2975042 HLA-A, 6p21.3 
  rs3129055, rs9258122 HLA-F, 6p21.3 
  rs29232 Gamma-aminobutyric acid b receptor 1 (GABBR1), 6p21.3 
Bei et al. (2010) 1,583 + 3,507 + 279 rs2860580 HLA-A, 6p21.3 
  rs2894207 HLA-B/C, 6p21.3 
  rs28421666 HLA-DQ/DR, 6p21.3 
  rs9510787 TNF receptor superfamily member 19 (TNFRSF19), 13q12 
  rs6774494 Myelodysplasia 1 and ecotropic viral insertion site 1 (MDS1-EVI1), 3q26 
  rs1412829 Cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/2B), 9p21 
Tang et al. (2012) 567 + 356 + 482 HLA-A 62Gln HLA-A*11:01 
  HLA-B HLA-B*13:01, HLA-B*55:02, HLA-B*38:02 
  −16Leu, 116Leu  
Chin et al. (2015) 184 + 260 rs11136697, HLA-A 99Cys HLA-A*02:07, HLA-A*11:01 
  rs1059520, HLA-A 145His HLA-A*11:01 
Cui et al. (2016a) 1,583 + 1,925 + 3,538 rs401681 Telomerase reverse transcriptase/cleft lip and palate transmembrane protein 1-like (TERT-CLPTM1L), 5p15 
  rs6498114 Class II MHC transactivator (CIITA), 16p13 
StudyCases (n)LocusGene
Ng et al. (2009) 111 + 168 rs2212020, rs189897 Integrin-α 9 (ITGA9), 3p21 
Tse et al. (2009) 277 + 339 + 296 rs2517713, rs2975042 HLA-A, 6p21.3 
  rs3129055, rs9258122 HLA-F, 6p21.3 
  rs29232 Gamma-aminobutyric acid b receptor 1 (GABBR1), 6p21.3 
Bei et al. (2010) 1,583 + 3,507 + 279 rs2860580 HLA-A, 6p21.3 
  rs2894207 HLA-B/C, 6p21.3 
  rs28421666 HLA-DQ/DR, 6p21.3 
  rs9510787 TNF receptor superfamily member 19 (TNFRSF19), 13q12 
  rs6774494 Myelodysplasia 1 and ecotropic viral insertion site 1 (MDS1-EVI1), 3q26 
  rs1412829 Cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/2B), 9p21 
Tang et al. (2012) 567 + 356 + 482 HLA-A 62Gln HLA-A*11:01 
  HLA-B HLA-B*13:01, HLA-B*55:02, HLA-B*38:02 
  −16Leu, 116Leu  
Chin et al. (2015) 184 + 260 rs11136697, HLA-A 99Cys HLA-A*02:07, HLA-A*11:01 
  rs1059520, HLA-A 145His HLA-A*11:01 
Cui et al. (2016a) 1,583 + 1,925 + 3,538 rs401681 Telomerase reverse transcriptase/cleft lip and palate transmembrane protein 1-like (TERT-CLPTM1L), 5p15 
  rs6498114 Class II MHC transactivator (CIITA), 16p13 

Abbreviation: HLA, human leukocyte antigen.

These findings corroborate links detected in the 1970s between NPC risk and certain alleles in the HLA region, which encodes proteins required for antigen presentation and other essential immune system functions (174, 175). NPC risk thus appears to be influenced by genetic variation in the ability of antigen-presenting cells to bind and present intracellular antigens, including those from EBV, to cytotoxic T cells—that is, the function of class I HLA molecules (encoded by HLA-A, HLA-B, and HLA-C). Although the identification of specific causal alleles is complicated by the high density of genes and strong linkage disequilibrium in the HLA region, consistent positive associations of NPC risk have been detected with HLA-A*0207 (in linkage disequilibrium with HLA-B*4601) and HLA-B*5801 (in linkage disequilibrium with HLA-A*3303), and an inverse association has consistently been found with HLA-A*1101 (in linkage disequilibrium with HLA-B*13; refs. 157, 176, 177). A contributing role of class II HLA molecules (encoded by HLA-DR, HLA-DQ, HLA-DM, and HLA-DP), which present extracellular antigens to helper T cells that in turn stimulate antibody-producing B cells, is also suggested by studies in Chinese, Tunisian, and Caucasian populations (178), as well as findings from one GWAS (168, 179), but not another GWAS (180), which found associations with the class I region but not the class II region.

Candidate-gene studies

Numerous epidemiologic studies of genetic susceptibility to NPC have evaluated various SNPs in genes involved in immune function, inflammation, DNA repair, biotransformation, and other pathways hypothesized to be involved in NPC development. Although many statistical associations have been reported, few have been detected consistently across multiple study populations, making it difficult to distinguish causal effects from chance findings. Given the substantial uncertainty concerning the impact of common genetic variants on NPC risk, candidate-gene studies are summarized here only briefly, focusing on SNPs with a sufficient number of published studies to prompt meta-analysis [despite the questionable validity and value of such meta-analyses themselves (181)] and selecting genes with a broad range of functions.

The cytochrome P450 (CYP) and glutathione-S-transferase (GST) gene families encode phase I and II xenobiotic metabolism enzymes involved in the biotransformation of chemicals such as N-nitrosamines, components of tobacco smoke, and other toxins. Meta-analyses including up to 12 case–control studies of NPC in relation to genetic polymorphisms in GSTM1 and GSTT1 found overall meta-ORs of approximately 1.4–1.5 for the GSTM1 null genotype and approximately 1.3–1.4 for the GSTT1 null genotype, including after restriction to Asians (182, 183). A meta-analysis of associations with genetic polymorphisms in CYP2E1 found significant positive associations of NPC risk with the RsaI/PstI variant (meta-OR = 2.7 under the recessive model), based on seven studies (six in Asians), and the DraI variant (meta-OR = 1.7 under the recessive model), based on three studies (184).

Genetic variants in DNA repair genes are also of natural interest as potential cancer risk factors. A meta-analysis of polymorphisms in the X-ray repair cross-complementing protein 1 gene (XRCC1) found a positive association of NPC risk with the Arg399Gln variant (meta-OR = 1.3 under the recessive model), based on 10 studies, but no association with the Arg194Trp and Arg280Gln variants (185). Results restricted to Asians were similar. A separate evaluation of the Thr241Met polymorphism in XRCC3 reported a meta-OR of 3.1 under the recessive model, based on four NPC case–control studies in Asians (186).

In a meta-analysis including 10 NPC case–control studies of the Arg72Pro polymorphism in the cell-cycle regulation/tumor suppressor gene TP53, the overall meta-OR was 1.5 under the recessive model, with a stronger association in Caucasians than Asians, although the meta-OR was significantly positive in both populations (187). The 1G>2G polymorphism at position −1607 in the matrix metalloproteinase-1 (MMP1) gene, which is involved in the degradation of interstitial collagens and can enhance tumor growth and invasion, exhibited a meta-OR of 0.61 under the homozygous model (meta-OR = 0.91 under the recessive model) based on six studies, with similar results based on the five studies of Asians (188). The meta-OR for the 8473 T>C polymorphism in the proinflammatory cyclooxygenase-2 (COX2) gene was 0.65 under the recessive model, based on three studies of NPC (two in Caucasians and one in Asians; ref. 189). Across four NPC case–control studies in Asian populations, for the -94 ATTG insertion/deletion polymorphism in the NFκB subunit 1 gene (NFKB1), the meta-OR was 0.78 under the recessive model (190).

The landscape of NPC epidemiology has shifted in recent years, with more powerful and in-depth genetic studies, and new findings from several rigorously designed population-based studies in high-incidence regions. Where consumption of Chinese-style salted fish was once one of the most prominent known risk factors for NPC, our recent results suggest that it has a more modest influence on NPC risk than previously estimated, especially for intake during adulthood. The pivotal roles of EBV infection and HLA-A and HLA-B class I genotypes remain clear, and recent investigations into both viral and host genetic variation have identified key polymorphisms that may explain a substantial proportion of NPC in southern China. Viral and host genetic factors provide the basis for promising NPC risk prediction models (e.g., refs. 31, 191–193), and EBV remains the foundation for developing new NPC screening strategies (e.g., ref. 194). Although causal, tobacco smoking appears to have a lesser impact on NPC development than on other head and neck cancers, especially squamous cell carcinomas. Otherwise, besides age, sex, and race/ethnicity, risk factors for NPC remain elusive (Table 2). Associations with indoor and outdoor air pollution merit further investigation due to the large potential population attributable risk from these widespread exposures, if causal. Occupational inhalation exposures, in contrast, are unlikely to account for a sizable fraction of NPC cases, even if causal. Collaborative pooled studies will be needed to achieve the statistical power required to reveal how viral, genetic, and environmental factors interact to cause NPC, and how intervention against modifiable characteristics can prevent it.

Table 2.

Risk factors and preventive factors for NPC.

Risk factorDirection of associationa
Well-confirmed risk factors 
 Older age (up to ∼60 years in high-incidence areas) ↑↑ 
 Male sex ↑ 
 Cantonese ethnic background ↑↑ 
 Tobacco smoke ↑ 
 Chinese-style salted fish (in early life) ↑ 
 Epstein–Barr virus infection (positive IgA serology) ↑↑ 
 First-degree family history of NPC ↑↑ 
 Certain HLA-A and HLA-B alleles ↑/↓ 
Possible risk factors, based on substantial data 
 Indoor air pollution ↑ 
 Other preserved foods ↑ 
 Fresh fruits and vegetables ↓ 
 Epstein–Barr virus sequence variation ↑↑ 
 Chronic respiratory tract infection/inflammation ↑ 
 HIV/AIDS ↑ 
 Occupational wood dust ↑ 
 Other types of occupational dust or smoke ↑ 
 Certain HLA-D alleles ↑/↓ 
Inconsistent findings 
 Alcohol ↑/– 
 Tea ↓/– 
 Outdoor air pollution ↑/– 
 Occupational formaldehyde ↑/– 
 Traditional herbal medicines ↑/↓/– 
Risk factorDirection of associationa
Well-confirmed risk factors 
 Older age (up to ∼60 years in high-incidence areas) ↑↑ 
 Male sex ↑ 
 Cantonese ethnic background ↑↑ 
 Tobacco smoke ↑ 
 Chinese-style salted fish (in early life) ↑ 
 Epstein–Barr virus infection (positive IgA serology) ↑↑ 
 First-degree family history of NPC ↑↑ 
 Certain HLA-A and HLA-B alleles ↑/↓ 
Possible risk factors, based on substantial data 
 Indoor air pollution ↑ 
 Other preserved foods ↑ 
 Fresh fruits and vegetables ↓ 
 Epstein–Barr virus sequence variation ↑↑ 
 Chronic respiratory tract infection/inflammation ↑ 
 HIV/AIDS ↑ 
 Occupational wood dust ↑ 
 Other types of occupational dust or smoke ↑ 
 Certain HLA-D alleles ↑/↓ 
Inconsistent findings 
 Alcohol ↑/– 
 Tea ↓/– 
 Outdoor air pollution ↑/– 
 Occupational formaldehyde ↑/– 
 Traditional herbal medicines ↑/↓/– 

Abbreviations: HLA, human leukocyte antigen; IgA, immunoglobulin A; NPC, nasopharyngeal carcinoma.

aArrows indicate the approximate magnitude of the relationship, although the magnitude can vary substantially depending on the intensity, duration, and other characteristics of exposure.

↑: slight to moderate increase in risk.

↑↑: moderate to large increase in risk.

↓: slight to moderate decrease in risk.

↓↓: moderate to large decrease in risk.

↑/↓: slight to moderate increase or decrease in risk, depending on genotype or exposure type.

–: no change in risk.

E.T. Chang reports grants from Sun Yat-sen University Cancer Center and Foundation for Chemistry Research and Initiatives during the conduct of the study, as well as other (i.e., salary) from Exponent outside the submitted work. No disclosures were reported by the other authors.

The authors thank Betty Dowd (Exponent) for her assistance with graphic design.

Funding support for this work was provided by the Sun Yat-sen University Cancer Center and by the Foundation for Chemistry Research and Initiatives (FCRI), a non-profit organization established by the American Chemistry Council, as an honorarium to Exponent. The FCRI was not involved in the conception, writing, or submission of this article, and did not review any portion of the article prior to journal submission or publication.

E.T. Chang is an employee of Exponent, an international science and engineering consulting company that provides consulting support to clients in industry, government, academia, and the private sector on some of the environmental exposures discussed in this review.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
Muir
CS
. 
Nasopharyngeal cancer–a historical vignette
.
CA Cancer J Clin
1983
;
33
:
180
5
.
2.
Ye
W
,
Chang
ET
,
Liu
Z
,
Liu
Q
,
Cai
Y
,
Zhang
Z
, et al
Development of a population-based cancer case-control study in southern China
.
Oncotarget
2017
;
8
:
87073
85
.
3.
Ferlay
J
,
Ervik
M
,
Lam
F
,
Colombet
M
,
Mery
L
,
Piñeros
M
, et al
,
editors
.
Global cancer observatory: cancer today
.
Lyon, France
:
International Agency for Research on Cancer (IARC)
; 
2018a
[accessed 2020 Oct 15]. Available from:
https://gco.iarc.fr/today.
4.
Bray
F
,
Colombet
M
,
Mery
L
,
Piñeros
M
,
Znaor
A
,
Zanetti
R
, et al
,
editors
.
Cancer incidence in five continents, Vol. XI (electronic version)
.
Lyon
:
International Agency for Research on Cancer
; 
2017
[accessed 2020 Oct 15]. Available from:
https://ci5.iarc.fr.
5.
Chan
JKC
,
Bray
F
,
McCarron
P
,
Foo
W
,
Lee
AWM
,
Yip
T
, et al
Nasopharyngeal carcinoma
.
In:
Barnes
L
,
Eveson
JW
,
Reichart
P
,
Sidransky
D
editors
.
World Health Organization classification of tumours. Pathology & genetics. Head and neck tumours
.
Lyon
:
International Agency for Research on Cancer (IARC)
; 
2005
.
p.
85
97
.
6.
Vaughan
TL
,
Shapiro
JA
,
Burt
RD
,
Swanson
GM
,
Berwick
M
,
Lynch
CF
, et al
Nasopharyngeal cancer in a low-risk population: defining risk factors by histological type
.
Cancer Epidemiol Biomarkers Prev
1996
;
5
:
587
93
.
7.
Li
CC
,
Yu
MC
,
Henderson
BE
. 
Some epidemiologic observations of nasopharyngeal carcinoma in Guangdong, People's Republic of China
.
Natl Cancer Inst Monogr
1985
;
69
:
49
52
.
8.
Wee
JTS
,
Ha
TC
,
Loong
SLE
,
Qian
C-N
. 
Is nasopharyngeal cancer really a "Cantonese cancer"?
Chin J Cancer
2010
;
29
:
517
26
.
9.
Mousavi
SM
,
Sundquist
J
,
Hemminki
K
. 
Nasopharyngeal and hypopharyngeal carcinoma risk among immigrants in Sweden
.
Int J Cancer
2010
;
127
:
2888
92
.
10.
Yu
WM
,
Hussain
SS
. 
Incidence of nasopharyngeal carcinoma in Chinese immigrants, compared with Chinese in China and South East Asia: review
.
J Laryngol Otol
2009
;
123
:
1067
74
.
11.
Parkin
DM
,
Iscovich
J
. 
Risk of cancer in migrants and their descendants in Israel: II. Carcinomas and germ-cell tumours
.
Int J Cancer
1997
;
70
:
654
60
.
12.
Flores
AD
,
Dickson
RI
,
Riding
K
,
Coy
P
. 
Cancer of the nasopharynx in British Columbia
.
Am J Clin Oncol
1986
;
9
:
281
91
.
13.
Buell
P
. 
Race and place in the etiology of nasopharyngeal cancer: a study based on California death certificates
.
Int J Cancer
1973
;
11
:
268
72
.
14.
Jeannel
D
,
Ghnassia
M
,
Hubert
A
,
Sancho-Garnier
H
,
Eschwège
F
,
Crognier
E
, et al
Increased risk of nasopharyngeal carcinoma among males of French origin born in Maghreb (north Africa)
.
Int J Cancer
1993
;
54
:
536
9
.
15.
Ferlay
J
,
Colombet
M
,
Bray
F
,
editors
.
Cancer incidence in five continents, CI5 I-X: IARC CancerBase No. 9 [Internet]
.
Lyon, France
:
International Agency for Research on Cancer (IARC)
; 
2018
-[accessed 2020 Oct 16]. Available from:
http://ci5.iarc.fr.
16.
Hsu
C
,
Shen
Y-C
,
Cheng
C-C
,
Hong
R-L
,
Chang
C-J
,
Cheng
A-L
. 
Difference in the incidence trend of nasopharyngeal and oropharyngeal carcinomas in Taiwan: implication from age-period-cohort analysis
.
Cancer Epidemiol Biomarkers Prev
2006
;
15
:
856
61
.
17.
Singapore Cancer Registry, 50 Years of Cancer Registration. Singapore Cancer Registry 50th Anniversary Monograph, 1968–2017
.
Singapore
:
Health Promotion Board
; 
2019
.
Available from:
https://www.nrdo.gov.sg/docs/librariesprovider3/default-document-library/thespore-cancerregistry_commerativebook_-1.pdf?sfvrsn=231fce6e_0.
18.
Wei
KR
,
Yu
YL
,
Yang
YY
,
Ji
MF
,
Yu
BH
,
Liang
ZH
, et al
Epidemiological trends of nasopharyngeal carcinoma in China
.
Asian Pac J Cancer Prev
2010
;
11
:
29
32
.
19.
Jia
W-H
,
Huang
Qi-H
,
Liao
J
,
Ye
W
,
Shugart
Yy
,
Liu
Q
, et al
Trends in incidence and mortality of nasopharyngeal carcinoma over a 20–25 year period (1978/1983–2002) in Sihui and Cangwu counties in southern China
.
BMC Cancer
2006
;
6
:
178
.
20.
Tse
LA
,
Yu
IT-S
,
Mang
OW-K
,
Wong
S-L
. 
Incidence rate trends of histological subtypes of nasopharyngeal carcinoma in Hong Kong
.
Br J Cancer
2006
;
95
:
1269
73
.
21.
SEER, Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER Research Limited-Field Data, 9 Registries, Nov 2019 Sub (1975–2017) - Linked To County Attributes - Time Dependent (1990–2017) Income/Rurality, 1969–2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2020, based on the November 2019 submission
; 
2020a
.
Available from:
https://seer.cancer.gov/data/.
22.
Argirion
I
,
Zarins
KR
,
Ruterbusch
JJ
,
Vatanasapt
P
,
Sriplung
H
,
Seymour
EK
, et al
Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States
.
Cancer
2020
;
126
:
121
30
.
23.
Klein
G
,
Klein
E
,
Kashuba
E
. 
Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes
.
Biochem Biophys Res Commun
2010
;
396
:
67
73
.
24.
IARC
. 
The evaluation of carcinogenic risks to humans [monograph on the internet]. Volume 100B. Biological agents
.
Lyon, France
:
International Agency for Research on Cancer (IARC)
; 
2012
.
p.
1
475
.
25.
Cancer Genome Atlas Research Network
. 
Comprehensive molecular characterization of gastric adenocarcinoma
.
Nature
2014
;
513
:
202
9
.
26.
Kangro
HO
,
Osman
HK
,
Lau
YL
,
Heath
RB
,
Yeung
CY
,
Ng
MH
. 
Seroprevalence of antibodies to human herpesviruses in England and Hong Kong
.
J Med Virol
1994
;
43
:
91
6
.
27.
Levine
R
,
Zhu
K
,
Gu
Y
,
Brann
E
,
Hall
I
,
Caplan
L
, et al
Self-reported infectious mononucleosis and 6 cancers: a population-based, case-control study
.
Scand J Infect Dis
1998
;
30
:
211
4
.
28.
Liu
Z
,
Fang
F
,
Chang
ET
,
Adami
H-O
,
Ye
W
. 
Sibship size, birth order and risk of nasopharyngeal carcinoma and infectious mononucleosis: a nationwide study in Sweden
.
Int J Epidemiol
2016
;
45
:
825
34
.
29.
da Costa
VG
,
Marques-Silva
AC
,
Moreli
ML
. 
The Epstein-Barr virus latent membrane protein-1 (LMP1) 30-bp deletion and XhoI-polymorphism in nasopharyngeal carcinoma: a meta-analysis of observational studies
.
Syst Rev
2015
;
4
:
46
.
30.
Xu
M
,
Yao
Y
,
Chen
H
,
Zhang
S
,
Cao
Su-M
,
Zhang
Z
, et al
Genome sequencing analysis identifies Epstein-Barr virus subtypes associated with high risk of nasopharyngeal carcinoma
.
Nat Genet
2019
;
51
:
1131
6
.
31.
Cui
Q
,
Feng
Fu-T
,
Xu
M
,
Liu
W-S
,
Yao
Y-Y
,
Xie
S-H
, et al
Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants
.
Oncotarget
2017
;
8
:
95066
74
.
32.
Coghill
AE
,
Hsu
W-L
,
Yang
Qi
,
Wang
C-P
,
Lou
P-J
,
Yu
KJ
, et al
Elevated antibodies against Epstein-Barr virus among individuals predicted to carry nasopharyngeal carcinoma susceptibility variants
.
J Gen Virol
2018
;
99
:
1268
73
.
33.
Pickard
A
,
Chen
C-J
,
Diehl
SR
,
Liu
M-Y
,
Cheng
Yu-J
,
Hsu
W-L
, et al
Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan
.
Int J Cancer
2004
;
111
:
117
23
.
34.
Qin
H-De
,
Jia
W-H
,
Zhang
L-L
,
Liu
Na
,
Zhou
X-Xi
,
Wang
M-H
, et al
Elevated Epstein-Barr virus seroreactivity among unaffected members of families with nasopharyngeal carcinoma
.
J Med Virol
2011
;
83
:
1792
8
.
35.
Hutajulu
SH
,
Ng
N
,
Jati
BR
,
Fachiroh
J
,
Herdini
C
,
Hariwiyanto
B
, et al
Seroreactivity against Epstein-Barr virus (EBV) among first-degree relatives of sporadic EBV-associated nasopharyngeal carcinoma in Indonesia
.
J Med Virol
2012
;
84
:
768
76
.
36.
Fogg
MH
,
Wirth
LJ
,
Posner
M
,
Wang
F
. 
Decreased EBNA-1-specific CD8+ T cells in patients with Epstein-Barr virus-associated nasopharyngeal carcinoma
.
Proc Natl Acad Sci U S A
2009
;
106
:
3318
23
.
37.
Chien
Y-C
,
Chen
J-Y
,
Liu
M-Y
,
Yang
H-I
,
Hsu
M-M
,
Chen
C-J
, et al
Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men
.
N Engl J Med
2001
;
345
:
1877
82
.
38.
Lanier
A
,
Bender
T
,
Talbot
M
,
Wilmeth
S
,
Tschopp
C
,
Henle
W
, et al
Nasopharyngeal carcinoma in Alaskan Eskimos Indians, and Aleuts: a review of cases and study of Epstein-Barr virus, HLA, and environmental risk factors
.
Cancer
1980
;
46
:
2100
6
.
39.
Zeng
Y
,
Zhang
LG
,
Wu
YC
,
Huang
YS
,
Huang
NQ
,
Li
JY
, et al
Prospective studies on nasopharyngeal carcinoma in Epstein-Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China
.
Int J Cancer
1985
;
36
:
545
7
.
40.
Henle
W
,
Ho
HC
,
Henle
G
,
Kwan
HC
. 
Antibodies to Epstein-Barr virus-related antigens in nasopharyngeal carcinoma. Comparison of active cases with long-term survivors
.
J Natl Cancer Inst
1973
;
51
:
361
9
.
41.
de Schryver
A
,
Klein
G
,
Henle
W
,
Henle
G
. 
EB virus-associated antibodies in Caucasian patients with carcinoma of the nasopharynx and in long-term survivors after treatment
.
Int J Cancer
1974
;
13
:
319
25
.
42.
Ji
M-F
,
Huang
Qi-H
,
Yu
X
,
Liu
Z
,
Li
X
,
Zhang
Li-F
, et al
Evaluation of plasma Epstein-Barr virus DNA load to distinguish nasopharyngeal carcinoma patients from healthy high-risk populations in Southern China
.
Cancer
2014
;
120
:
1353
60
.
43.
Coghill
AE
,
Bu
W
,
Nguyen
H
,
Hsu
W-L
,
Yu
KJ
,
Lou
P-J
, et al
High levels of antibody that neutralize B-cell infection of Epstein-Barr virus and that bind EBV gp350 are associated with a lower risk of nasopharyngeal carcinoma
.
Clin Cancer Res
2016
;
22
:
3451
7
.
44.
Coghill
AE
,
Bu
W
,
Hsu
W-L
,
Nguyen
H
,
Yu
KJ
,
Chien
Y-C
, et al
Evaluation of total and IgA-specific antibody targeting Epstein-Barr virus glycoprotein 350 and nasopharyngeal carcinoma risk
.
J Infect Dis
2018
;
218
:
886
91
.
45.
Hording
U
,
Nielsen
HW
,
Daugaard
S
,
Albeck
H
. 
Human papillomavirus types 11 and 16 detected in nasopharyngeal carcinomas by the polymerase chain reaction
.
Laryngoscope
1994
;
104
:
99
102
.
46.
Lin
Z
,
Khong
B
,
Kwok
S
,
Cao
H
,
West
RB
,
Le
Q-T
, et al
Human papillomavirus 16 detected in nasopharyngeal carcinomas in white Americans but not in endemic Southern Chinese patients
.
Head Neck
2014
;
36
:
709
14
.
47.
Ye
Y-F
,
Xiang
YQ
,
Fang
F
,
Gao
R
,
Zhang
LF
,
Xie
SH
, et al
Hepatitis B virus infection and risk of nasopharyngeal carcinoma in Southern China
.
Cancer Epidemiol Biomarkers Prev
2015
;
24
:
1766
73
.
48.
Mahale
P
,
Sturgis
EM
,
Tweardy
DJ
,
Ariza-Heredia
EJ
,
Torres
HA
. 
Association between hepatitis C virus and head and neck cancers
.
J Natl Cancer Inst
2016
;
108
:
djw035
.
49.
Shebl
FM
,
Bhatia
K
,
Engels
EA
. 
Salivary gland and nasopharyngeal cancers in individuals with acquired immunodeficiency syndrome in United States
.
Int J Cancer
2010
;
126
:
2503
8
.
50.
Engels
EA
,
Pfeiffer
RM
,
Fraumeni
JF
,
Kasiske
BL
,
Israni
AK
,
Snyder
JJ
, et al
Spectrum of cancer risk among US solid organ transplant recipients
.
JAMA
2011
;
306
:
1891
901
.
51.
Huo
Z
,
Li
C
,
Xu
X
,
Ge
F
,
Wang
R
,
Wen
Y
, et al
Cancer risks in solid organ transplant recipients: results from a comprehensive analysis of 72 cohort studies
.
Oncoimmunology
2020
;
9
:
1848068
.
52.
Grulich
AE
,
van Leeuwen
MT
,
Falster
MO
,
Vajdic
CM
. 
Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis
.
Lancet
2007
;
370
:
59
67
.
53.
IARC
. 
The evaluation of carcinogenic risks to humans [monograph on the Internet]. Volume 100E. Personal habits and indoor combustions
.
Lyon, France
:
International Agency for Research on Cancer (IARC)
: 
2012
.
p.
1
538
.
54.
Xue
W-Q
,
Qin
H-D
,
Ruan
H-L
,
Shugart
YY
,
Jia
W-H
. 
Quantitative association of tobacco smoking with the risk of nasopharyngeal carcinoma: a comprehensive meta-analysis of studies conducted between 1979 and 2011
.
Am J Epidemiol
2013
;
178
:
325
38
.
55.
Long
M
,
Fu
Z
,
Li
P
,
Nie
Z
. 
Cigarette smoking and the risk of nasopharyngeal carcinoma: a meta-analysis of epidemiological studies
.
BMJ Open
2017
;
7
:
e016582
.
56.
Hsu
W-L
,
Chien
Y-C
,
Huang
Y-T
,
Yu
KJ
,
Ko
J-Y
,
Lin
C-Y
, et al
Cigarette smoking increases the risk of nasopharyngeal carcinoma through the elevated level of IgA antibody against Epstein-Barr virus capsid antigen: a mediation analysis
.
Cancer Med
2020
;
9
:
1867
76
.
57.
Hu
T
,
Lin
C-Y
,
Xie
S-H
,
Chen
G-H
,
Lu
Yu-Q
,
Ling
W
, et al
Smoking can increase nasopharyngeal carcinoma risk by repeatedly reactivating Epstein-Barr Virus: an analysis of a prospective study in southern China
.
Cancer Med
2019
;
8
:
2561
71
.
58.
Xu
F-H
,
Xiong
D
,
Xu
Ya-F
,
Cao
Su-M
,
Xue
W-Q
,
Qin
H-De
, et al
An epidemiological and molecular study of the relationship between smoking, risk of nasopharyngeal carcinoma, and Epstein-Barr virus activation
.
J Natl Cancer Inst
2012
;
104
:
1396
410
.
59.
Chang
ET
,
Liu
Z
,
Hildesheim
A
,
Liu
Q
,
Cai
Y
,
Zhang
Z
, et al
Active and passive smoking and risk of nasopharyngeal carcinoma: a population-based case-control study in Southern China
.
Am J Epidemiol
2017
;
185
:
1272
80
.
60.
Yang
XR
,
Diehl
S
,
Pfeiffer
R
,
Chen
CJ
,
Hsu
WL
,
Dosemeci
M
, et al
Evaluation of risk factors for nasopharyngeal carcinoma in high-risk nasopharyngeal carcinoma families in Taiwan
.
Cancer Epidemiol Biomarkers Prev
2005
;
14
:
900
5
.
61.
West
S
,
Hildesheim
A
,
Dosemeci
M
. 
Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: results from a case-control study
.
Int J Cancer
1993
;
55
:
722
7
.
62.
Fachiroh
J
,
Sangrajrang
S
,
Johansson
M
,
Renard
H
,
Gaborieau
V
,
Chabrier
A
, et al
Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand
.
Cancer Causes Control
2012
;
23
:
1995
2002
.
63.
Feng
B-J
,
Khyatti
M
,
Ben-Ayoub
W
,
Dahmoul
S
,
Ayad
M
,
Maachi
F
, et al
Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa
.
Br J Cancer
2009
;
101
:
1207
12
.
64.
Oudjehih
M
,
Deltour
I
,
Bouhidel
ML
,
Bouhidel
A
,
Marref
A
,
Luzon
V
, et al
Smokeless tobacco use, cigarette smoking, and upper aerodigestive tract cancers: a case-control study in the Batna Region, Algeria, 2008–2011
.
Tob Use Insights
2020
;
13
:
1179173x20902239
.
65.
Zheng
Ym
,
Tuppin
P
,
Hubert
A
,
Jeannel
D
,
Pan
Yj
,
Zeng
Y
, et al
Environmental and dietary risk factors for nasopharyngeal carcinoma: a case-control study in Zangwu County, Guangxi, China
.
Br J Cancer
1994
;
69
:
508
14
.
66.
Guo
X
,
Johnson
RC
,
Deng
H
,
Liao
J
,
Guan
Li
,
Nelson
GW
, et al
Evaluation of nonviral risk factors for nasopharyngeal carcinoma in a high-risk population of Southern China
.
Int J Cancer
2009
;
124
:
2942
7
.
67.
He
Y-Q
,
Xue
W-Q
,
Shen
G-P
,
Tang
L-L
,
Zeng
Yi-X
,
Jia
W-H
. 
Household inhalants exposure and nasopharyngeal carcinoma risk: a large-scale case-control study in Guangdong, China
.
BMC Cancer
2015
;
15
:
1022
.
68.
Adoga
AA
,
Kokong
DD
,
Nimkur
TL
,
Ma'an
ND
. 
Environmental and life-style related risk factors for sinonasal and nasopharyngeal malignancies among a prospective cohort in Jos, Nigeria
.
Int J Otolaryngol
2018
;
2018
:
8524861
.
69.
Jeannel
D
,
Hubert
A
,
De Vathaire
F
,
Ellouz
R
,
Camoun
M
,
Ben Salem
M
, et al
Diet, living conditions and nasopharyngeal carcinoma in Tunisia–a case-control study
.
Int J Cancer
1990
;
46
:
421
5
.
70.
Shanmugaratnam
K
,
Tye
CY
,
Goh
EH
,
Chia
KB
. 
Etiological factors in nasopharyngeal carcinoma: a hospital-based, retrospective, case-control, questionnaire study
.
IARC Sci Publ
1978
;
20
:
199
212
.
71.
Geser
A
,
Charnay
N
,
Day
NE
,
de-The
G
,
Ho
HC
. 
Environmental factors in the etiology of nasopharyngeal carcinoma: report on a case-control study in Hong Kong
.
IARC Sci Publ
1978
;
20
:
213
29
.
72.
Yu
MC
,
Ho
JH
,
Lai
SH
,
Henderson
BE
. 
Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: report of a case-control study in Hong Kong
.
Cancer Res
1986
;
46
:
956
61
.
73.
Yu
MC
,
Mo
CC
,
Chong
WX
,
Yeh
FS
,
Henderson
BE
. 
Preserved foods and nasopharyngeal carcinoma: a case-control study in Guangxi, China
.
Cancer Res
1988
;
48
:
1954
9
.
74.
Yu
MC
,
Garabrant
DH
,
Huang
T-Bo
,
Henderson
BE
. 
Occupational and other non-dietary risk factors for nasopharyngeal carcinoma in Guangzhou, China
.
Int J Cancer
1990
;
45
:
1033
9
.
75.
Friborg
JT
,
Yuan
J-M
,
Wang
R
,
Koh
W-P
,
Lee
H-P
,
Yu
MC
. 
Incense use and respiratory tract carcinomas: a prospective cohort study
.
Cancer
2008
;
113
:
1676
84
.
76.
Chen
Y
,
Chang
ET
,
Liu
Z
,
Liu
Q
,
Cai
Y
,
Zhang
Z
, et al
Residence characteristics and risk of nasopharyngeal carcinoma in southern China: a population-based case-control study
.
Environ Int
2021
;
151
:
106455
.
77.
Fan
H-C
,
Chen
C-Y
,
Hsu
Yi-C
,
Chou
R-H
,
Teng
C-LJ
,
Chiu
C-H
, et al
Increased risk of incident nasopharyngeal carcinoma with exposure to air pollution
.
PLoS One
2018
;
13
:
e0204568
.
78.
Huang
H-C
,
Tantoh
DM
,
Hsu
S-Yi
,
Nfor
ON
,
Frank
C-FL
,
Lung
C-C
, et al
Association between coarse particulate matter (PM10–2.5) and nasopharyngeal carcinoma among Taiwanese men
.
J Investig Med
2020
;
68
:
419
24
.
79.
Yang
T
,
Liu
Y
,
Zhao
W
,
Chen
Z
,
Deng
J
. 
Association of ambient air pollution with nasopharyngeal carcinoma incidence in ten large Chinese cities, 2006–2013
.
Int J Environ Res Public Health
2020
;
17
:
1824
.
80.
IARC
. 
The evaluation of carcinogenic risks to humans [monograph on the Internet]
.
Volume 56. Some naturally occurring substances: food Items and constituents, heterocyclic aromatic amines and mycotoxins
.
Lyon, France
:
International Agency for Research on Cancer (IARC)
; 
1993
.
p.
1
599
.
81.
Armstrong
RW
,
Imrey
PB
,
Lye
MS
,
Armstrong
MJ
,
Yu
MC
,
Sani
S
. 
Nasopharyngeal carcinoma in Malaysian Chinese: salted fish and other dietary exposures
.
Int J Cancer
1998
;
77
:
228
35
.
82.
Yuan
J-M
,
Wang
X-Li
,
Xiang
Y-B
,
Gao
Yu-T
,
Ross
RK
,
Yu
MC
. 
Preserved foods in relation to risk of nasopharyngeal carcinoma in Shanghai, China
.
Int J Cancer
2000
;
85
:
358
63
.
83.
Jia
W-H
,
Luo
X-Yu
,
Feng
B-J
,
Ruan
H-L
,
Bei
J-X
,
Liu
W-S
, et al
Traditional Cantonese diet and nasopharyngeal carcinoma risk: a large-scale case-control study in Guangdong, China
.
BMC Cancer
2010
;
10
:
446
.
84.
Gallicchio
L
,
Matanoski
G
,
Tao
XG
,
Chen
L
,
Lam
TK
,
Boyd
K
, et al
Adulthood consumption of preserved and nonpreserved vegetables and the risk of nasopharyngeal carcinoma: a systematic review
.
Int J Cancer
2006
;
119
:
1125
35
.
85.
Ning
J-P
,
Yu
MC
,
Wang
Q-S
,
Henderson
BE
. 
Consumption of salted fish and other risk factors for nasopharyngeal carcinoma (NPC) in Tianjin, a low-risk region for NPC in the People's Republic of China
.
J Natl Cancer Inst
1990
;
82
:
291
6
.
86.
Farrow
DC
,
Vaughan
TL
,
Berwick
M
,
Lynch
CF
,
Swanson
GM
,
Lyon
JL
. 
Diet and nasopharyngeal cancer in a low-risk population
.
Int J Cancer
1998
;
78
:
675
9
.
87.
Barrett
D
,
Ploner
A
,
Chang
ET
,
Liu
Z
,
Zhang
C-X
,
Liu
Q
, et al
Past and recent salted fish and preserved food intakes are weakly associated with nasopharyngeal carcinoma risk in adults in Southern China
.
J Nutr
2019
;
149
:
1596
605
.
88.
Yu
MC
,
Huang
TB
,
Henderson
BE
. 
Diet and nasopharyngeal carcinoma: a case-control study in Guangzhou, China
.
Int J Cancer
1989
;
43
:
1077
82
.
89.
Liu
Y-T
,
Dai
J-J
,
Xu
C-H
,
Lu
Y-K
,
Fan
Yu-Y
,
Zhang
X-L
, et al
Greater intake of fruit and vegetables is associated with lower risk of nasopharyngeal carcinoma in Chinese adults: a case-control study
.
Cancer Causes Control
2012
;
23
:
589
99
.
90.
Polesel
J
,
Serraino
D
,
Negri
E
,
Barzan
L
,
Vaccher
E
,
Montella
M
, et al
Consumption of fruit, vegetables, and other food groups and the risk of nasopharyngeal carcinoma
.
Cancer Causes Control
2013
;
24
:
1157
65
.
91.
Feng
XX
,
Wang
MX
,
Li
M
,
Tang
X
,
Jiang
H
,
Wang
R
, et al
Citrus fruit intake and the risk of nasopharyngeal carcinoma
.
Asia Pac J Clin Nutr
2019
;
28
:
783
92
.
92.
Lee
HP
,
Gourley
L
,
Duffy
SW
,
Esteve
J
,
Lee
J
,
Day
NE
. 
Preserved foods and nasopharyngeal carcinoma: a case-control study among Singapore Chinese
.
Int J Cancer
1994
;
59
:
585
90
.
93.
Polesel
J
,
Negri
E
,
Serraino
D
,
Parpinel
M
,
Barzan
L
,
Libra
M
, et al
Dietary intakes of carotenoids and other nutrients in the risk of nasopharyngeal carcinoma: a case-control study in Italy
.
Br J Cancer
2012
;
107
:
1580
3
.
94.
Abe
M
,
Shivappa
N
,
Ito
H
,
Oze
I
,
Abe
T
,
Shimizu
Y
, et al
Dietary inflammatory index and risk of upper aerodigestive tract cancer in Japanese adults
.
Oncotarget
2018
;
9
:
24028
40
.
95.
Accardi
G
,
Shivappa
N
,
Di Maso
M
,
Hébert
JR
,
Fratino
L
,
Montella
M
, et al
Dietary inflammatory index and cancer risk in the elderly: a pooled-analysis of Italian case-control studies
.
Nutrition
2019
;
63–64
:
205
10
.
96.
Shivappa
N
,
Hébert
JR
,
Zucchetto
A
,
Montella
M
,
Libra
M
,
Garavello
W
, et al
Increased risk of nasopharyngeal carcinoma with increasing levels of diet-associated inflammation in an Italian case-control study
.
Nutr Cancer
2016
;
68
:
1123
30
.
97.
Edefonti
V
,
Nicolussi
F
,
Polesel
J
,
Bravi
F
,
Bosetti
C
,
Garavello
W
, et al
Nutrient-based dietary patterns and nasopharyngeal cancer: evidence from an exploratory factor analysis
.
Br J Cancer
2015
;
112
:
446
54
.
98.
Wang
C
,
Lin
X-L
,
Fan
Yu-Y
,
Liu
Y-T
,
Zhang
X-L
,
Lu
Y-K
, et al
Diet quality scores and risk of nasopharyngeal carcinoma in Chinese adults: a case-control study
.
Nutrients
2016
;
8
:
112
.
99.
Lo
Y-Li
,
Pan
W-H
,
Hsu
W-L
,
Chien
Y-C
,
Chen
J-Y
,
Hsu
M-M
, et al
Partial least square discriminant analysis discovered a dietary pattern inversely associated with nasopharyngeal carcinoma risk
.
PLoS One
2016
;
11
:
e0155892
.
100.
Turati
F
,
Bravi
F
,
Polesel
J
,
Bosetti
C
,
Negri
E
,
Garavello
W
, et al
Adherence to the Mediterranean diet and nasopharyngeal cancer risk in Italy
.
Cancer Causes Control
2017
;
28
:
89
95
.
101.
Huang
TT
, et al
Dietary patterns and risk of nasopharyngeal carcinoma: a population-based case-control study in southern China
.
Am J Clin Nutr
(
in press
).
102.
Hildesheim
A
,
West
S
,
DeVeyra
E
,
De Guzman
MF
,
Jurado
A
,
Jones
C
, et al
Herbal medicine use, Epstein-Barr virus, and risk of nasopharyngeal carcinoma
.
Cancer Res
1992
;
52
:
3048
51
.
103.
Lin
C
,
Cao
Su-M
,
Chang
ET
,
Liu
Z
,
Cai
Y
,
Zhang
Z
, et al
Chinese nonmedicinal herbal diet and risk of nasopharyngeal carcinoma: a population-based case-control study
.
Cancer
2019
;
125
:
4462
70
.
104.
Zeng
Y
,
Zhong
JM
,
Mo
YK
,
Miao
XC
. 
Epstein-Barr virus early antigen induction in Raji cells by Chinese medicinal herbs
.
Intervirology
1983
;
19
:
201
4
.
105.
Chen
L
,
Gallicchio
L
,
Boyd-Lindsley
K
,
Tao
X
,
Robinson
K
,
Lam
TK
, et al
Alcohol consumption and the risk of nasopharyngeal carcinoma: a systematic review
.
Nutr Cancer
2009
;
61
:
1
15
.
106.
Du
T
,
Chen
K
,
Zheng
S
,
Bao
M
,
Huang
Y
,
Wu
K
. 
Association between alcohol consumption and risk of nasopharyngeal carcinoma: a comprehensive meta-analysis of epidemiological studies
.
Alcohol Clin Exp Res
2019
;
43
:
2262
73
.
107.
Friborg
JT
,
Yuan
J-M
,
Wang
R
,
Koh
W-P
,
Lee
H-P
,
Yu
MC
. 
A prospective study of tobacco and alcohol use as risk factors for pharyngeal carcinomas in Singapore Chinese
.
Cancer
2007
;
109
:
1183
91
.
108.
Li
W
,
Ray
RM
,
Gao
DL
,
Fitzgibbons
ED
,
Seixas
NS
,
Camp
JE
, et al
Occupational risk factors for nasopharyngeal cancer among female textile workers in Shanghai, China
.
Occup Environ Med
2006
;
63
:
39
44
.
109.
Feng
R
,
Chang
ET
,
Liu
Q
,
Cai
Y
,
Zhang
Z
,
Chen
G
, et al
Intake of alcohol and tea and risk of nasopharyngeal carcinoma: a population- based case-control study in southern China
.
Cancer Epidemiol Biomarkers Prev
2021
;
30
:
545
53
.
110.
Hsu
W-L
,
Pan
W-H
,
Chien
Y-C
,
Yu
KJ
,
Cheng
Yu-J
,
Chen
J-Y
, et al
Lowered risk of nasopharyngeal carcinoma and intake of plant vitamin, fresh fish, green tea and coffee: a case-control study in Taiwan
.
PLoS One
2012
;
7
:
e41779
.
111.
Ruan
H-L
,
Xu
F-H
,
Liu
W-S
,
Feng
Qi-S
,
Chen
Li-Z
,
Zeng
Yi-X
, et al
Alcohol and tea consumption in relation to the risk of nasopharyngeal carcinoma in Guangdong, China
.
Front Med China
2010
;
4
:
448
56
.
112.
Chung
SD
,
Wu
CS
,
Lin
HC
,
Hung
SH
. 
Association between allergic rhinitis and nasopharyngeal carcinoma: a population-based study
.
Laryngoscope
2014
;
124
:
1744
9
.
113.
Lin
C
,
Lin
S-W
,
Weng
S-F
,
Lin
Y-S
. 
Subsequent risk of nasopharyngeal carcinoma among patients with allergic rhinitis: a nationwide population-based cohort study
.
Head Neck
2014
;
37
:
413
7
.
114.
Hung
SH
,
Chen
PY
,
Lin
HC
,
Ting
J
,
Chung
SD
. 
Association of rhinosinusitis with nasopharyngeal carcinoma: a population-based study
.
Laryngoscope
2014
;
124
:
1515
20
.
115.
Yuan
J-M
,
Wang
X-Li
,
Xiang
Y-B
,
Gao
Yu-T
,
Ross
RK
,
Yu
MC
. 
Non-dietary risk factors for nasopharyngeal carcinoma in Shanghai, China
.
Int J Cancer
2000
;
85
:
364
9
.
116.
Beachler
DC
,
Engels
EA
. 
Chronic sinusitis and risk of head and neck cancer in the US elderly population
.
JAMA Otolaryngol Head Neck Surg
2017
;
143
:
25
31
.
117.
Wu
EL
,
Riley
CA
,
Hsieh
M-C
,
Marino
MJ
,
Wu
X-C
,
McCoul
ED
. 
Chronic sinonasal tract inflammation as a precursor to nasopharyngeal carcinoma and sinonasal malignancy in the United States
.
Int Forum Allergy Rhinol
2017
;
7
:
786
93
.
118.
Huang
W-Y
,
Lin
C-C
,
Jen
Y-M
,
Lin
K-T
,
Yang
M-H
,
Chen
C-M
, et al
Association between adult otitis media and nasopharyngeal cancer: a nationwide population-based cohort study
.
Radiother Oncol
2012
;
104
:
338
42
.
119.
Kim
HJ
,
Ahn
HS
,
Kang
T
,
Bachert
C
,
Song
W-J
. 
Nasal polyps and future risk of head and neck cancer: a nationwide population-based cohort study
.
J Allergy Clin Immunol
2019
;
144
:
1004
10
.
120.
Xiao
X
,
Zhang
Z
,
Chang
ET
,
Liu
Z
,
Liu
Q
,
Cai
Y
, et al
Medical history, medication use, and risk of nasopharyngeal carcinoma
.
Am J Epidemiol
2018
;
187
:
2117
25
.
121.
Huang
Po-W
,
Chiou
Yi-R
,
Wu
S-L
,
Liu
Ju-C
,
Chiou
K-R
. 
Risk of nasopharyngeal carcinoma in patients with chronic rhinosinusitis: a nationwide propensity score matched study in Taiwan
.
Asia Pac J Clin Oncol
2020
[Online ahead of print]
.
122.
Liu
Z
,
Chang
ET
,
Liu
Q
,
Cai
Y
,
Zhang
Z
,
Chen
G
, et al
Oral hygiene and risk of nasopharyngeal carcinoma-a population-based case-control study in China
.
Cancer Epidemiol Biomarkers Prev
2016
;
25
:
1201
7
.
123.
Debelius
JW
,
Huang
T
,
Cai
Y
,
Ploner
A
,
Barrett
D
,
Zhou
X
, et al
Subspecies niche specialization in the oral microbiome is associated with nasopharyngeal carcinoma risk
.
mSystems
2020
;
5
:
e00065
20
.
124.
Tseng
K-S
,
Lin
C
,
Lin
Y-S
,
Weng
S-F
. 
Risk of head and neck cancer in patients with diabetes mellitus: a retrospective cohort study in Taiwan
.
JAMA Otolaryngol Head Neck Surg
2014
;
140
:
746
53
.
125.
Peng
Y-S
,
Lin
Jr-R
,
Cheng
Bi-H
,
Ho
C
,
Lin
Y-H
,
Shen
C-H
, et al
Incidence and relative risk for developing cancers in women with gestational diabetes mellitus: a nationwide cohort study in Taiwan
.
BMJ Open
2019
;
9
:
e024583
.
126.
Zucchetto
A
,
Taborelli
M
,
Bosetti
C
,
Montella
M
,
La Vecchia
C
,
Franchin
G
, et al
Metabolic disorders and the risk of nasopharyngeal carcinoma: a case-control study in Italy
.
Eur J Cancer Prev
2018
;
27
:
180
3
.
127.
Hsieh
S-H
,
Chiou
W-Ko
,
Wang
M-H
,
Lin
J-D
. 
Association of body weight with the risk for malignancies in hospitalized patients with or without diabetes mellitus in Taiwan
.
J Investig Med
2014
;
62
:
37
42
.
128.
Yen
Y-C
,
Lin
C
,
Lin
S-W
,
Lin
Y-S
,
Weng
S-F
. 
Effect of metformin on the incidence of head and neck cancer in diabetics
.
Head Neck
2015
;
37
:
1268
73
.
129.
Tseng
CH
. 
Metformin and risk of developing nasopharyngeal cancer in patients with type 2 diabetes mellitus
.
Metabolism
2018
;
85
:
223
6
.
130.
IARC
. 
The evaluation of carcinogenic risks to humans [monograph on the Internet]
.
Volume 100F. Chemical agents and related occupations
.
Lyon, France
:
International Agency for Research on Cancer (IARC)
; 
2012
.
p.
1
599
.
131.
IARC
. 
The evaluation of carcinogenic risks to humans [monograph on the Internet]
.
Volume 100C. Arsenic, metals, fibres, and dusts
.
Lyon, France
:
International Agency for Research on Cancer
; 
2012
.
p.
1
501
.
132.
ECHA, Substance Evaluation Conclusion as required by REACH Article 48 and Evaluation Report for Formaldehyde, EC No 200-001-8, CAS No 50-00-0
.
Evaluating Member State: France. Co-evaluating Member State: The Netherlands. Dated: 7 June 2019
; 
2019
.
Available at
: https://echa.europa.eu/documents/10162/cc0acabf-6e82-f2ed-5dbe-8058f48ce6c4.
133.
Swenberg
JA
,
Kerns
WD
,
Mitchell
RI
,
Gralla
EJ
,
Pavkov
KL
. 
Induction of squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor
.
Cancer Res
1980
;
40
:
3398
402
.
134.
Albert
RE
,
Sellakumar
AR
,
Laskin
S
,
Kuschner
M
,
Nelson
N
,
Snyder
CA
. 
Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat
.
J Natl Cancer Inst
1982
;
68
:
597
603
.
135.
Armstrong
RW
,
Imrey
PB
,
Lye
MS
,
Armstrong
MJ
,
Yu
MC
,
Sani
S
. 
Nasopharyngeal carcinoma in Malaysian Chinese: occupational exposures to particles, formaldehyde and heat
.
Int J Epidemiol
2000
;
29
:
991
8
.
136.
Xie
S-H
,
Yu
IT-S
,
Tse
LAh
,
Au
JSK
,
Lau
JSM
. 
Occupational risk factors for nasopharyngeal carcinoma in Hong Kong Chinese: a case-referent study
.
Int Arch Occup Environ Health
2017
;
90
:
443
9
.
137.
Hildesheim
A
,
Dosemeci
M
,
Chan
CC
,
Chen
CJ
,
Cheng
YJ
,
Hsu
MM
, et al
Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma
.
Cancer Epidemiol Biomarkers Prev
2001
;
10
:
1145
53
.
138.
Bachand
AM
,
Mundt
KA
,
Mundt
DJ
,
Montgomery
RR
. 
Epidemiological studies of formaldehyde exposure and risk of leukemia and nasopharyngeal cancer: a meta-analysis
.
Crit Rev Toxicol
2010
;
40
:
85
100
.
139.
Siew
SS
,
Kauppinen
T
,
Kyyrönen
P
,
Heikkila
P
,
Pukkala
E
. 
Occupational exposure to wood dust and formaldehyde and risk of nasal, nasopharyngeal, and lung cancer among Finnish men
.
Cancer Manag Res
2012
;
4
:
223
32
.
140.
Meyers
AR
,
Pinkerton
LE
,
Hein
MJ
. 
Cohort mortality study of garment industry workers exposed to formaldehyde: update and internal comparisons
.
Am J Ind Med
2013
;
56
:
1027
39
.
141.
Sernia
S
,
Di Folco
F
,
Altrudo
P
,
Sbriccoli
B
,
Sestili
C
,
Colamesta
V
, et al
[Risk of nasopharyngeal cancer, leukemia and other tumors in a cohort of employees and students potentially exposed to (FA) formaldehyde in university laboratories]
.
Clin Ter
2016
;
167
:
43
7
.
142.
Siew
SS
,
Martinsen
JI
,
Kjaerheim
K
,
Sparén
P
,
Tryggvadottir
L
,
Weiderpass
E
, et al
Occupational exposure to wood dust and risk of nasal and nasopharyngeal cancer: a case-control study among men in four nordic countries-With an emphasis on nasal adenocarcinoma
.
Int J Cancer
2017
;
141
:
2430
6
.
143.
Pira
E
,
Romano
C
,
Verga
F
,
La Vecchia
C
. 
Mortality from lymphohematopoietic neoplasms and other causes in a cohort of laminated plastic workers exposed to formaldehyde
.
Cancer Causes Control
2014
;
25
:
1343
9
.
144.
Chen
YF
,
Chang
ET
,
Liu
Q
,
Cai
Y
,
Zhang
Z
,
Chen
G
, et al
Occupational exposures and risk of nasopharyngeal carcinoma in a high-risk area: a population-based case-control study
.
Cancer
2021
[Online ahead of print]
.
145.
Blair
A
,
Stewart
P
,
O'Berg
M
,
Gaffey
W
,
Walrath
J
,
Ward
J
, et al
Mortality among industrial workers exposed to formaldehyde
.
J Natl Cancer Inst
1986
;
76
:
1071
84
.
146.
Hauptmann
M
,
Lubin
JH
,
Stewart
PA
,
Hayes
RB
,
Blair
A
. 
Mortality from solid cancers among workers in formaldehyde industries
.
Am J Epidemiol
2004
;
159
:
1117
30
.
147.
Beane Freeman
LE
,
Blair
A
,
Lubin
JH
,
Stewart
PA
,
Hayes
RB
,
Hoover
RN
, et al
Mortality from solid tumors among workers in formaldehyde industries: an update of the NCI cohort
.
Am J Ind Med
2013
;
56
:
1015
26
.
148.
Marsh
GM
,
Morfeld
P
,
Zimmerman
SD
,
Liu
Y
,
Balmert
LC
. 
An updated re-analysis of the mortality risk from nasopharyngeal cancer in the National Cancer Institute formaldehyde worker cohort study
.
J Occup Med Toxicol
2016
;
11
:
8
.
149.
Marsh
GM
,
Morfeld
P
,
Collins
JJ
,
Symons
J
. 
Issues of methods and interpretation in the National Cancer Institute formaldehyde cohort study
.
J Occup Med Toxicol
2014
;
9
:
22
.
150.
Möhner
M
,
Liu
Y
,
Marsh
GM
. 
New insights into the mortality risk from nasopharyngeal cancer in the National Cancer Institute formaldehyde worker cohort study
.
J Occup Med Toxicol
2019
;
14
:
4
.
151.
Möhner
M
,
Wendt
A
. 
A diagnostic bias might be a much simpler explanation for the apparently elevated risk for nasopharyngeal cancer with respect to formaldehyde
.
J Occup Med Toxicol
2016
;
11
:
54
.
152.
Beigzadeh
Z
,
Pourhassan
B
,
kalantary
S
,
Golbabaei
F
. 
Occupational exposure to wood dust and risk of nasopharyngeal cancer: a systematic review and meta-analysis
.
Environ Res
2019
;
171
:
170
6
.
153.
E
M
,
Yin
J
,
Jin
W
,
Mao
Y
,
Wu
Q
,
Qiu
J
. 
Wood dust exposure and risks of nasopharyngeal carcinoma: a meta-analysis
.
Eur J Public Health
2020
;
30
:
817
22
.
154.
Ng
TP
. 
A case-referent study of cancer of the nasal cavity and sinuses in Hong Kong
.
Int J Epidemiol
1986
;
15
:
171
5
.
155.
Zheng
W
,
McLaughlin
JK
,
Gao
YT
,
Gao
RN
,
Blot
WJ
. 
Occupational risks for nasopharyngeal cancer in Shanghai
.
J Occup Med
1992
;
34
:
1004
7
.
156.
Zeng
YX
,
Jia
WH
. 
Familial nasopharyngeal carcinoma
.
Semin Cancer Biol
2002
;
12
:
443
50
.
157.
Bei
JX
,
Jia
WH
,
Zeng
YX
. 
Familial and large-scale case-control studies identify genes associated with nasopharyngeal carcinoma
.
Semin Cancer Biol
2012
;
22
:
96
106
.
158.
Friborg
J
,
Wohlfahrt
J
,
Koch
A
,
Storm
H
,
Olsen
OR
,
Melbye
M
. 
Cancer susceptibility in nasopharyngeal carcinoma families–a population-based cohort study
.
Cancer Res
2005
;
65
:
8567
72
.
159.
Jia
W-H
,
Feng
B-J
,
Xu
Z-Li
,
Zhang
X-S
,
Huang
P
,
Huang
Li-Xi
, et al
Familial risk and clustering of nasopharyngeal carcinoma in Guangdong
,
Cancer
2004
;
101
:
363
9
.
160.
Yu
KJ
,
Hsu
W-L
,
Chiang
C-Ju
,
Cheng
Yu-J
,
Pfeiffer
RM
,
Diehl
SR
, et al
Cancer patterns in nasopharyngeal carcinoma multiplex families in Taiwan
.
Int J Cancer
2009
;
124
:
1622
5
.
161.
Liu
Z
,
Chang
ET
,
Liu
Q
,
Cai
Y
,
Zhang
Z
,
Chen
G
, et al
Quantification of familial risk of nasopharyngeal carcinoma in a high-incidence area
.
Cancer
2017
;
123
:
2716
25
.
162.
Jia
W-H
,
Collins
A
,
Zeng
Yi-X
,
Feng
B-J
,
Yu
X-J
,
Huang
Li-Xi
, et al
Complex segregation analysis of nasopharyngeal carcinoma in Guangdong, China: evidence for a multifactorial mode of inheritance (complex segregation analysis of NPC in China)
.
Eur J Hum Genet
2005
;
13
:
248
52
.
163.
Lu
S-J
,
Day
NE
,
Degos
L
,
Lepage
V
,
Wang
P-C
,
Chan
So-Ha
, et al
Linkage of a nasopharyngeal carcinoma susceptibility locus to the HLA region
.
Nature
1990
;
346
:
470
1
.
164.
Feng
B-J
,
Huang
W
,
Shugart
YY
,
Lee
MK
,
Zhang
F
,
Xia
J-C
, et al
Genome-wide scan for familial nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4
.
Nat Genet
2002
;
31
:
395
9
.
165.
Xiong
W
,
Zeng
ZY
,
Xia
JH
,
Xia
K
,
Shen
SR
,
Li
XL
, et al
A susceptibility locus at chromosome 3p21 linked to familial nasopharyngeal carcinoma
.
Cancer Res
2004
;
64
:
1972
4
.
166.
Hu
Li-Fu
,
Qiu
Q-H
,
Fu
S-M
,
Sun
Di
,
Magnusson
K
,
He
B
, et al
A genome-wide scan suggests a susceptibility locus on 5p 13 for nasopharyngeal carcinoma
.
Eur J Hum Genet
2008
;
16
:
343
9
.
167.
Dai
J
,
Shen
W
,
Wen
W
,
Chang
J
,
Wang
T
,
Chen
H
, et al
Estimation of heritability for nine common cancers using data from genome-wide association studies in Chinese population
.
Int J Cancer
2017
;
140
:
329
36
.
168.
Bei
J-X
,
Li
Yi
,
Jia
W-H
,
Feng
B-J
,
Zhou
G
,
Chen
Li-Z
, et al
A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci
.
Nat Genet
2010
;
42
:
599
603
.
169.
Ng
CC
,
Yew
PY
,
Puah
SM
,
Krishnan
G
,
Yap
LF
,
Teo
SH
, et al
A genome-wide association study identifies ITGA9 conferring risk of nasopharyngeal carcinoma
.
J Hum Genet
2009
;
54
:
392
7
.
170.
Tang
M
,
Lautenberger
JA
,
Gao
X
,
Sezgin
E
,
Hendrickson
SL
,
Troyer
JL
, et al
The principal genetic determinants for nasopharyngeal carcinoma in China involve the HLA class I antigen recognition groove
.
PLoS Genet
2012
;
8
:
e1003103
.
171.
Tse
Ka-Po
,
Su
W-H
,
Chang
K-P
,
Tsang
N-M
,
Yu
C-J
,
Tang
P
, et al
Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3
.
Am J Hum Genet
2009
;
85
:
194
203
.
172.
Chin
YM
,
Mushiroda
T
,
Takahashi
A
,
Kubo
M
,
Krishnan
G
,
Yap
L-F
, et al
HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese
.
Int J Cancer
2015
;
136
:
678
87
.
173.
Cui
Q
,
Feng
Qi-S
,
Mo
H-Y
,
Sun
J
,
Xia
Y-F
,
Zhang
H
, et al
An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma
.
Hum Mol Genet
2016
;
25
:
3626
34
.
174.
Simons
MJ
,
Chan
SH
,
Wee
GB
,
Shanmugaratnam
K
,
Goh
EH
,
Ho
JH
, et al
Nasopharyngeal carcinoma and histocompatibility antigens
.
IARC Sci Publ
1978
;
20
:
271
82
.
175.
Simons
MJ
,
Day
NE
,
Wee
GB
,
Shanmugaratnam
K
,
Ho
HC
,
Wong
SH
, et al
Nasopharyngeal carcinoma V: immunogenetic studies of Southeast Asian ethnic groups with high and low risk for the tumor
.
Cancer Res
1974
;
34
:
1192
5
.
176.
Goldsmith
DB
,
West
TM
,
Morton
R
. 
HLA associations with nasopharyngeal carcinoma in Southern Chinese: a meta-analysis
.
Clin Otolaryngol Allied Sci
2002
;
27
:
61
7
.
177.
Hildesheim
A
,
Wang
CP
. 
Genetic predisposition factors and nasopharyngeal carcinoma risk: a review of epidemiological association studies, 2000–2011: Rosetta Stone for NPC: genetics, viral infection, and other environmental factors
.
Semin Cancer Biol
2012
;
22
:
107
16
.
178.
Yang
H
,
Yu
K
,
Zhang
R
,
Li
J
,
Wei
X
,
Zhang
Y
, et al
The HLA-DRB1 allele polymorphisms and nasopharyngeal carcinoma
.
Tumour Biol
2016
;
37
:
7119
28
.
179.
Wang
T-M
,
Zhou
T
,
He
Y-Q
,
Xue
W-Q
,
Zhang
J-Bo
,
Zheng
X-H
, et al
Fine-mapping of HLA class I and class II genes identified two independent novel variants associated with nasopharyngeal carcinoma susceptibility
.
Cancer Med
2018
;
7
:
6308
16
.
180.
Liu
Z
,
Derkach
A
,
Yu
KJ
,
Yeager
M
,
Chang
YS
,
Chen
CJ
, et al
Patterns of human leukocyte antigen class I and class II associations and cancer
.
Cancer Res
2020
;
81
:
1148
52
.
181.
Ioannidis
JP
. 
The mass production of redundant, misleading, and conflicted systematic reviews and meta-analyses
.
Milbank Q
2016
;
94
:
485
514
.
182.
Zhao
Y
,
Wang
Y
,
Wu
X
,
Wang
J
,
Zhang
L
,
Jia
Y
, et al
Quantitative assessment of the association between glutathione S-transferase M1 polymorphism and the risk of developing nasopharyngeal cancer
.
Oncol Lett
2016
;
11
:
373
8
.
183.
Liu
RR
,
Chen
J-C
,
Li
M-D
,
Li
T
,
Tan
Y
,
Zhang
M
. 
A meta-analysis of glutathione S-transferase M1 and T1 genetic polymorphism in relation to susceptibility to nasopharyngeal carcinoma
.
Int J Clin Exp Med
2015
;
8
:
10626
32
.
184.
Yao
K
,
Qin
H
,
Gong
L
,
Zhang
R
,
Li
L
. 
CYP2E1 polymorphisms and nasopharyngeal carcinoma risk: a meta-analysis
.
Eur Arch Otorhinolaryngol
2017
;
274
:
253
9
.
185.
Lin
J
,
Ye
Q
,
Wang
Y
,
Wang
Y
,
Zeng
Y
. 
Association between XRCC1 single-nucleotide polymorphisms and susceptibility to nasopharyngeal carcinoma: an update meta-analysis
.
Medicine
2018
;
97
:
e11852
.
186.
Cui
Q
,
Zuo
X-Yu
,
Lian
Yi-F
,
Feng
Qi-S
,
Xia
Y-F
,
He
C-Y
, et al
Association between XRCC3 Thr241Met polymorphism and nasopharyngeal carcinoma risk: evidence from a large-scale case-control study and a meta-analysis
.
Tumour Biol
2016
;
37
:
14825
30
.
187.
Sahu
SK
,
Chakrabarti
S
,
Roy
SD
,
Baishya
N
,
Reddy
RR
,
Suklabaidya
S
, et al
Association of p53 codon72 Arg>Pro polymorphism with susceptibility to nasopharyngeal carcinoma: evidence from a case-control study and meta-analysis
.
Oncogenesis
2016
;
5
:
e225
.
188.
Li
Z
,
Ge
H
,
Xie
Y-G
,
Xie
G-Y
,
Lv
C
. 
Matrix metalloproteinase-1 (MMP1) polymorphism is associated with lowered risk of nasopharyngeal carcinoma in Asian population
.
Cell Biochem Biophys
2015
;
71
:
999
1004
.
189.
Li
Q
,
Ma
C
,
Zhang
Z
,
Chen
S
,
Zhi
W
,
Zhang
L
, et al
Association between cyclooxygenase-2 (COX-2) 8473 T > C polymorphism and cancer risk: a meta-analysis and trial sequential analysis
.
BMC Cancer
2018
;
18
:
847
.
190.
Li
L
,
Zhang
ZT
. 
Genetic association between NFKBIA and NFKB1 gene polymorphisms and the susceptibility to head and neck cancer: a meta-analysis
.
Dis Markers
2019
;
2019
:
6523837
.
191.
Lee
MH
,
Huang
Y-H
,
Coghill
AE
,
Liu
Z
,
Yu
KJ
,
Hsu
W-L
, et al
Epstein-Barr virus (EBV) based nasopharyngeal carcinoma (NPC) risk prediction scores are elevated in NPC multiplex family members compared to the general population in Taiwan
.
J Infect Dis
2021
;
223
:
441
4
.
192.
Chen
H
,
Chen
S
,
Lu
J
,
Wang
X
,
Li
J
,
Li
L
, et al
Multiparametric detection of antibodies against different EBV antigens to predict risk for nasopharyngeal carcinoma in a high-risk population of China
.
Cancer Prev Res
2017
;
10
:
542
50
.
193.
Chen
GH
,
Liu
Z
,
Ji
M-F
,
Pfeiffer
RM
,
Huang
Q-H
,
Lu
Y-Q
, et al
Prospective assessment of a nasopharyngeal carcinoma risk score in a population undergoing screening
.
Int J Cancer
2020
[Online ahead of print]
.
194.
Chan
KCA
,
Woo
JKS
,
King
A
,
Zee
BCY
,
Lam
WKJ
,
Chan
SL
, et al
Analysis of plasma Epstein-Barr virus DNA to screen for nasopharyngeal cancer
.
N Engl J Med
2017
;
377
:
513
22
.