Abstract 5075: B-cell expression of AICDA and MME [CALLA, CD10] is predictive of a subsequent non-Hodgkin lymphoma diagnosis
Authors: Hussain Shehnaz K. , Epeldegui Marta , Magpantay Larry I. , Breen Elizabeth Crabb , Knowlton Emilee , Wolinksy Steven , Jacobson Lisa P. , Bream Jay H. , Detels Roger , Zhang Zuo-Feng , Martinez-Maza Otoniel 
Published: May 2015

Background: Mounting evidence from epidemiologic studies of serum biomarkers highlights the importance of inflammation and immune activation preceding the diagnosis of B-cell non-Hodgkin lymphoma (NHL). Although chronic B-cell hyperactivation is likely involved in the pathogenesis of NHL, an important gap in knowledge remains present as the source and targets of these inflammatory and immune activation associated factors are mainly undefined. Targeted studies of B-cell gene expression can help fill this gap, further define the immune environment from which these tumors arise, and assist in identifying biomarkers for early detection of B-cell NHLs.

Methods: This study was based in a large national cohort of HIV+ men, the Multicenter AIDS Cohort Study, who are at increased risk for developing NHL. 144 HIV+ B-cell NHL cases were matched to 144 HIV+ controls on follow-up time and sample availability. B-cells isolated from viably frozen peripheral blood mononuclear cells, collected 2 to 13 years (median 4.7 years) prior to NHL diagnosis or control match date, were used to measure messenger RNA (mRNA) levels of 16 molecules that are associated with B-cell activation, using the Quantigene® Plex 2.0 Assay Kit (Affymetrix) on the Luminex platform. Expression levels were normalized by the geomean of five housekeeping genes. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression for gene expression categorized as detectable versus undetectable.

Results: Activation-induced cytidine deaminase (AICDA) was detected in 8.3% of cases and 2.8% of controls, OR=3.7, 95% CI=1.0-13.1. Membrane metallo-endopeptidase (MME) was detected in 59.7% of cases and 29.9% of controls, OR=3.9, 95% CI=2.2-6.8. The AICDA and MME associations with NHL were similar across subgroups of site, EBV tumor status, and lag time between sample collection and NHL diagnosis date. AICDA, but not MME, was more strongly associated with NHL among those who were the least immunosuppressed (higher CD4+ T cell count and low HIV RNA levels). In subgroup analyses, CD40 ligand (CD40LG) expression was associated with NHL with a time lag time of &lt;6 years, OR=3.0, 95% CI=1.0-9.3, and Interleukin-6 (IL6) expression was associated with NHL among those with a CD4+ T cell count &lt;300, OR=3.9, 95% CI=0.9-17.

Interpretation & Conclusions: AICDA expression is essential for antibody specificity and diversity but its aberrant expression has been implicated in lymphomagenesis. MME is a signature marker of B-cell NHLs of germinal center origin and has previously been associated with NHL survival. We found that AICDA and MME expression precedes the clinical diagnosis of NHL in an HIV+ cohort. Additionally, late CD40LG expression and IL6 expression among the more severely immunosuppressed individuals were associated with NHL risk in this study. These molecules should be studied further for possible early detection and clinical utility.

Citation Format: Shehnaz K. Hussain, Marta Epeldegui, Larry I. Magpantay, Elizabeth Crabb Breen, Emilee Knowlton, Steven Wolinksy, Lisa P. Jacobson, Jay H. Bream, Roger Detels, Zuo-Feng Zhang, Otoniel Martinez-Maza. B-cell expression of AICDA and MME [CALLA, CD10] is predictive of a subsequent non-Hodgkin lymphoma diagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5075. doi:10.1158/1538-7445.AM2014-5075