AN EPIDEMIOLOGICAL STUDY ON NASOPHARYNGEAL CARCINOMA

Nasopharyngeal carcinoma (NPC) is a malignancy known for its unique geographic and ethnic distribution characterized by particularly high incidence in southern China, Southeast Asia, and North and East Africa, but being rare in the rest of the world. Its etiology has remained enigmatic and the accumulated evidence suggests that genetic predisposition, environmental factors, and infection with Epstein-Barr virus (EBV) are involved. Nevertheless, the association between environmental exposures and NPC carcinogenesis remains largely elusive to date, and how environmental risk factors interact with EBV in the development of NPC has been rarely studied. In addition, oral microbiome is emerging as a vital factor contributing to carcinogenic processes, but its role in NPC is largely unknown. The overall aim of this thesis is to provide more solid evidence and precise insights into the etiology of NPC, with focus on the associations of NPC with environmental, viral, and other microbial factors. To address these knowledge gaps, we carried out a large-scale populationbased case-control study entitled NPC Genes, Environment, and EBV (NPCGEE) in southern China from 2010 to 2014. In short, 2,554 histopathologically confirmed, incident NPC cases, and 2,648 controls frequency matched to cases on age, sex and geographic area from general population were recruited. In Study I, we investigated the magnitude and pattern of associations between NPC and various residential exposures. Based on the NPCGEE study questionnaire data of a lifelong residential history, we found poor residential conditions including living in inferior housing types, using less clean fuels for cooking, house with poor ventilation, using untreated water sources, exposure to smoke when cooking, burning incense, and residential proximity to a factory area, were associated with a higher risk of NPC, and the associations were notably stronger for exposures at young ages. In Study II, we examined the relationship of NPC risk with occupational exposures based also on the NPCGEE study. With the analysis of the complete occupational history data, we found significantly elevated risk of NPC associated with exposures to broad categories of occupational pollutants, including dusts, chemical vapors, exhausts/smokes, and acids/alkalis. These associations were primarily explained by 14 subtypes of occupational agents within the above-mentioned broad categories. Moreover, the strengths of the associations were generally stronger with increasing duration of exposure. In Study III, we assessed whether there is an association between environmental factors and EBV reactivation, a critical step in the NPC carcinogenesis, in the healthy population controls of the NPCGEE study. Overall, we found no associations between EBV reactivation and extensive environmental factors, including alcohol or tea drinking, a history of chronic ear/nose/throat diseases, use of medications or herbs, consumption of salted fish or other preserved foods, oral hygiene, sibship structure, and various residential and occupational exposures. Cigarette smoking is the only factor associated with EBV reactivation. In Study IV, we investigated the relationship between oral fungal microbiome and NPC status using Internal Transcribed Spacer (ITS)-2 sequencing in a subset of NPCGEE study samples (538 NPC patients, 537 controls). We found a significantly reduced fungal community richness and diversity in NPC patients compared with those in controls, and the global fungal community compositions significantly differed between cases and controls. Furthermore, a number of differentially abundant oral fungal organisms in NPC cases and healthy controls were identified. In conclusion, findings from this thesis work support that individuals exposed to both residential and occupational risk factors are at increased risk of NPC. Most environmental factors, except for cigarette smoking, are not likely to induce EBV reactivation; other mechanisms such as host genetic and viral variations in the EBV reactivation deserve to be further studied. Dysbiotic oral mycobiome characterized by reduced community richness and diversity, as well as an increased abundance in pathogenic fungi and a decrease in commensal fungi may contribute to the development of NPC. LIST OF SCIENTIFIC PAPERS This thesis is based on the following papers, which will be referred to in the content by their Roman numerals (I-IV). * Contribute equally. I. Chen Y, Chang ET, Liu Z, Liu Q, Cai Y, Zhang Z, Chen G, Huang QH, Xie SH, Cao SM, Jia WH, Zheng Y, Li Y, Lin L, Ernberg I, Zhao H, Feng R, Huang G, Zeng Y, Zeng YX, Adami HO, Ye W. Residence characteristics and risk of nasopharyngeal carcinoma in southern China: a population-based case-control study. Environment International, 2021, 151:106455. II. Chen Y, Chang ET, Liu Q, Cai Y, Zhang Z, Chen G, Huang QH, Xie SH, Cao SM, Jia WH, Zheng Y, Li Y, Lin L, Ernberg I, Wang D, Chen W, Feng R, Huang G, Zeng YX, Adami HO, Ye W. Occupational exposures and risk of nasopharyngeal carcinoma in a high-risk area: a population-based casecontrol study. Cancer, 2021, 127(15):2724-2735. III. Chen Y, Chang ET, Liu Q, Cai Y, Zhang Z, Chen G, Huang QH, Xie SH, Cao SM, Jia WH, Zheng Y, Li Y, Lin L, Ernberg I, Huang G, Zeng YX, Adami HO, Ye W. Environmental risk factors for Epstein-Barr virus reactivation in a high-risk area for nasopharyngeal carcinoma: a populationbased study. Manuscript submitted. IV. Chen Y * , Li W * , Chang ET, Debelius JW, Manoharan L, Zhang Z, Zheng Y, Li Y, Huang G, Adami HO, Knight R, Cai Y, Ye W. Oral fungal profiling and risk of nasopharyngeal carcinoma: a population-based case-control study. Manuscript.