Abstract 2538: GB virus C viremia and subsequent risk of non-Hodgkin lymphoma in the PLCO screening trial.
Authors: Chang Cindy , Stapleton Jack , Klinzman Donna , Larson Lars , Katki Hormuzd , Purdue Mark , Engels Eric A. 
Published: August 2014

Abstract
Background: Immune disturbance and chronic infections contribute to the development of non-Hodgkin lymphoma (NHL). GB virus C (GBV-C), a flavivirus, causes chronic asymptomatic infection in 1-2% of blood donors. Retrospective case-control studies have demonstrated associations between GBV-C viremia and NHL, but the prevalence of GBV-C could be artifactually high in NHL cases due to prior blood transfusions or disease-related immunosuppression and viral reactivation.
Methods: We conducted a case-control study nested in the U.S. Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. Using incidence density sampling, NHL cases were each matched to 2 controls on sex, race, and age and calendar year at cohort entry. Pre-diagnostic sera were assessed for GBV-C RNA in matched sets, with the laboratory blinded to case-control status. GBV RNA positivity was determined by a consensus algorithm incorporating results of 5 reverse transcriptase PCR assays. Odds ratios (ORs) for NHL overall and NHL subtypes were calculated using conditional and unconditional logistic regression, respectively.
Results: 658 NHL cases and 1316 controls were included. GBV-C RNA was detected in 37 subjects (1.9%). Notably, in contrast to the low prevalence in study subjects, blinded testing concurrently found GBV-C RNA in 24 of 25 (96%) positive quality control (QC) samples but also 14 of 25 (56%) of negative QC samples, likely reflecting contamination when the QC samples had been prepared. Nonetheless, among subjects GBV-C RNA tended to be more commonly detected in cases than controls (2.6% vs. 1.5%, OR 1.73, 95%CI 0.90-3.34, p=0.10). The association with NHL was strongest over longer latency intervals, with ORs (95%CI) of 1.56 (0.58-4.18), 0.88 (0.26-2.99), and 6.00 (1.21-29.7) for GBV-C RNA detected 0-1.0, 1.1-4.0, and 4.1+ years, respectively, before diagnosis/selection. Among NHL subtypes, we observed non-significant associations with GBV-C RNA for diffuse large B-cell lymphoma (OR 1.84, 95%CI 0.62-5.45), follicular lymphoma (2.29, 0.67-7.85), and chronic lymphocytic leukemia (2.15, 0.94-4.94).
Conclusions: GBV-C viremia was associated with a non-significant increased risk of NHL in a U.S. general population cohort. The presence of an association more than 4 years after detection of GBV-C RNA argues against bias related to NHL treatment or immunosuppression in cases, and lends support to a possible etiologic relationship. Detection of low-level GBV-C viremia was challenging, and contamination during sample preparation likely led to a high prevalence of RNA positivity in negative QC samples. Contamination should not have led to preferentially higher positivity in cases vs. controls, but we are undertaking additional confirmatory testing. Samples will also be assayed for infection with HIV and hepatitis C virus, which are proven viral causes of NHL and are more common in GBV-C infected individuals.
Citation Format: Cindy Chang, Jack Stapleton, Donna Klinzman, Lars Larson, Hormuzd Katki, Mark Purdue, Eric A. Engels. GB virus C viremia and subsequent risk of non-Hodgkin lymphoma in the PLCO screening trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2538. doi:10.1158/1538-7445.AM2013-2538