Background: Infections with some viruses, including HIV and Epstein-Barr Virus (EBV) in immunocompromised individuals, are known risk factors for specific subtypes of non-Hodgkin lymphoma (NHL). Epidemiological studies have also provided evidence that hepatitis viruses, and EBV in immunocompetent individuals, may also be associated with NHL. There are limited population-based prospective studies with pre-diagnostic blood samples that have comprehensively evaluated viral biomarkers and NHL risk in East Asians, in whom the descriptive characteristics of NHL and the prevalence of certain viral infections differ compared to Western populations.

Methods: We conducted a nested case-control study of 214 NHL cases and 214 controls from three population-based prospective cohorts in Shanghai and Singapore. Cases and controls were individually matched by age, sex, date of blood draw, and cohort. Antibodies to 21 antigens associated with the evaluated viruses (herpesviruses, Hepatitis B (HBV) and C (HCV), and polyomaviruses) were measured in plasma/serum using fluorescent bead-based multiplex serology. Conditional logistic regression was used to evaluate associations between viral antibody levels measured as median fluorescence intensity and NHL.

Results: For herpesviruses, an increased risk of NHL was observed for higher compared to lower early antigen diffuse (EA-D) (OR = 2.2, 95% CI = 1.2-4.1) and BZLF1-encoded replication activator (ZEBRA) (OR = 2.2, 95% CI = 1.0-4.9) antibodies (rsp = +0.5) associated with EBV. An increased risk of NHL was also observed among those seropositive for the intermediate-early 1A antigen (OR = 1.9, 95% CI = 1.0-3.3; rsp with EBV antibodies = +0.2) associated with human herpesvirus-6 (HHV-6). For hepatitis viruses, a significant NHL risk was observed for higher compared to lower antibodies to the HBV-associated core (HBc) antigen (OR = 1.8, 95% CI = 1.1-3.1), and this risk was particularly apparent in those with the highest HBc and EBV EA-D antibody levels (OR = 4.2, 95% CI = 1.4-12.7) compared to the lowest. Seropositivity to HCV was low (1.4% cases; 0.9% controls). No associations with NHL risk were observed for individual polyomaviruses (BK, JC, TSV, MCV). Discussion: Our study of serologic markers of infection and NHL risk in three prospective population-based studies of Chinese individuals suggests a role of specific viral agents in lymphomagenesis. The findings for EBV are consistent with some data from Western cohorts and indicate that EBV reactivation may be associated with NHL risk in the Chinese general population. HHV-6 is a lymphotropic virus that has been observed in some retrospective studies to be associated with lymphoma, but to our knowledge has not previously been associated with NHL prospectively in the general population. HBV is endemic to regions of East Asia, including China, and our data suggest that high levels of antibodies to the HBc antigen may be a marker for NHL risk.

Citation Format: Bryan A. Bassig, Angelika Michel, Xiao-Ou Shu, Woon-Puay Koh, Yu-Tang Gao, Lesley M. Butler, Mark Purdue, Yong-Bing Xiang, Jennifer Adams-Haduch, Renwei Wang, Nicole Brenner, Tim Waterboer, Martina Willhauck-Fleckenstein, Bu-Tian Ji, H. Dean Hosgood, Charles S. Rabkin, Jason Y.Y. Wong, Jinming Zhang, Wei Hu, Gong Yang, Wong-Ho Chow, Michael Pawlita, Wei Zheng, Jian-Min Yuan, Qing Lan, Nathaniel Rothman. Serologic markers of infection and risk of non-Hodgkin lymphoma in a pooled prospective study of three Chinese cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4245. doi:10.1158/1538-7445.AM2017-4245