Etiology and early detection of nasopharyngeal carcinoma : an epidemiological approach

Abstract: Nasopharyngeal carcinoma (NPC) is a rare malignancy worldwide, but it is endemic in a few areas including southern China, Southeast Asia, North Africa, and the Arctic. The underlying mechanisms behind this remarkable geographic distribution remain unclear. Although Epstein-Barr virus (EBV) infection has been suggested as a necessary cause of undifferentiated NPC, EBV itself is not sufficient to cause this malignancy. Other co-factors, such as environmental risk factors, and/or genetic susceptibility, may interact with EBV to play a role in the carcinogenesis of NPC. Survival rates differ significantly between NPC patients in early stages and late stages. Due to the close associations between EBV infection and NPC risk, EBV-related biomarkers have been used for early detection and screening for NPC has been conducted in a few high-incidence areas. However, the cost-effectiveness of this approach has not been demonstrated. Pilot efforts have highlighted that identification of additional biomarkers is needed to improve early detection rate and reduce the mortality rate of NPC in high-incidence populations. The aim of this thesis is to study the association of early-life social environment, oral hygiene, and family history with the risk of NPC, and to utilize an affinity proteomic approach to identify biomarkers that can potentially facilitate the early detection. In Study I, we investigated associations between childhood family structure, in terms of sibship size and number of older/younger siblings, and the risk of NPC or infectious mononucleosis (IM, another EBV-associated disease) in Sweden, an NPC low-incidence area. For each outcome, a nested case-control study was conducted within the Swedish national health and population registers, including 251 NPC cases, 11,314 IM cases, and five population controls per case matched by sex and year of birth. Clearly contrasting findings were observed between NPC and IM risk. We detected a monotonically increased risk of NPC with a larger sibship size (P trend = 0.006), especially with an increasing number of older siblings. For example, the odds ratio (OR) of NPC for those with three or more siblings compared with no siblings was 2.03 (95% confidence interval [CI]: 1.23, 3.35). In contrast, we detected a lower risk of IM among subjects with a larger sibship size, and more older/younger siblings. We concluded that early-life social environment could contribute to NPC pathogenesis in non-endemic areas. Earlier infection with EBV might be associated with an elevated risk of NPC, which is further supported by the clearly contrasting findings between NPC and IM. In Study II, we estimated the associations between oral hygiene and NPC risk in a high-incidence area. We conducted a population-based case-control study in southern China between 2010 and 2014, with a total of 2528 newly diagnosed NPC cases aged 20-74, and 2596 randomly selected controls. Controls were frequency matched to the age and sex distribution of the cases by geographic region. Based on questionnaire information, we found an increased risk of NPC with a higher number of filled teeth. Compared with those having no filled teeth, subjects having 1 to 3 and more than 3 filled teeth had adjusted ORs of 1.25 (95% CI: 1.06, 1.49) and 1.55 (95% CI: 1.13, 2.12), respectively (P trend = 0.002). In contrast, more frequent tooth brushing was inversely associated with the risk of NPC. We concluded that poor oral health could be associated with an elevated risk of NPC. Prospective cohort studies with a comprehensive measurement on oral health condition are needed to confirm our findings and explore the underlying mechanisms. Absolute NPC risks in the general population with and without a family history of NPC in NPC-endemic geographic regions, where the great majority of NPC cases occur worldwide, are largely unknown. In Study III, we utilized family data from the aforementioned population-based case-control study in southern China and found that subjects with a first-degree family history of NPC were at a greater than 4-fold higher risk for NPC, compared to those without such a history, whereas a family history of other malignancies did not confer an increased risk of NPC. The excess risk was higher for a maternal than a paternal history and slightly stronger for a sibling than a parental history, and for a sororal than a fraternal history. Among first-degree relatives of cases, the cumulative risk of NPC up to age 74 years was 3.7%, whereas that among relatives of controls was 0.9%. Cumulative risk was higher in siblings than in parents among relatives of cases, whereas no such difference was noted among relatives of controls. The affinity proteomic approach is valuable for biomarker validation and identification. In Study IV, we utilized plasma samples from 174 NPC cases and 175 community-based controls from Taiwan to identify biomarkers that could potentially facilitate early detection of NPC. We established a panel of eight such biomarkers, including proteins encoded by the genes CCNB1, KDR, PDGFB, LGALS1, HAS1, LY6K, IL2RA, and CXCL10. The combination of these eight markers showed promising value to distinguish early-stage NPC patients from controls (areas under the receiver operating characteristic curves = 0.808, 95% CI: 0.745, 0.871). Additional studies with prospectively collected biospecimens are warranted to examine the use of these plasma biomarkers in the early detection of NPC.