Combined Overexpression of Bcl-2 and SOCS3 Is Associated with Decreased Survival in a Cohort of Patients with De Novo Follicular Lymphoma.
Authors: Krishnadasan Ravitharan , Bifulco Carlo , Rodov Sofya , Kim Julie , Vanasse K. Gary J. 
Published: April 2020

Abstract
Follicular lymphomas (FL) comprise approximately twenty-five percent of all cases of non-Hodgkin’s lymphomas (NHL) in humans and are marked by a highly variable clinical course, ranging from indolent to rapidly progressive disease. The genetic hallmark of FL is t(14;18), resulting in deregulated expression of Bcl-2 and abrogation of the majority of apoptotic pathways in B and T lymphocytes. Data suggest that while t(14;18) is sufficient to initiate an oncogenic pathway, Bcl-2 alone is a relatively weak oncogene and requires additional cooperating genetic lesions for neoplastic transformation to occur. We previously demonstrated that Bcl-2 overexpression is associated with overexpression of the suppressor of cytokine signaling-3 (SOCS3) gene in a group of patients with de novo FL. In the current study, to determine whether SOCS3 overexpression has prognostic significance in FL, we performed a retrospective cohort study utilizing de novo FL lymph node tissue banked at Yale University. Eligibility criteria included subjects with FL tissue diagnosed as either histologic Grades I or II and harboring t(14;18)+. Subjects with transformed FL at presentation, HIV, other malignancy, or chronic autoimmune disorders were excluded. Subjects were segregated into two cohorts based on standard immunohistochemistry using SOCS3 and Bcl-2 antisera on FL tissue: Cohort 1 harboring combined overexpression of Bcl-2 and SOCS3 within the follicular center cell region and Cohort 2 harboring sole overexpression of Bcl-2. Immunostaining of germinal center B cells from benign hyperplastic tonsil tissue was used as a negative control for SOCS3 and Bcl-2 expression. Medical record review was performed to determine survival time from the date of initial diagnosis and to calculate the Follicular Lymphoma International Prognostic Index (FLIPI). Eighty-two subjects met eligibility criteria and had medical records available for review. Of these, 42 overexpressed both Bcl-2 and SOCS3 and 40 expressed Bcl-2 alone. Median survival in Cohort 1 was 8 years (95% CI 3.68, 12.32) compared to a median survival of 16.5 years (95% CI 14.56, 20.44) for Cohort 2 (Kaplan Meier survival analysis; p=0.01 log rank test). FLIPI score was not significantly different between the two cohorts. The decrease in survival in Cohort 1 (harboring combined overexpression of Bcl-2 and SOC3) remained statistically significant after adjustment for the FLIPI score (Cox Regression Analysis, p=0.01). Transformation to high grade NHL occurred in 8 of 42 (19%) and 2 of 40 (5%) subjects in Cohort 1 and Cohort 2, respectively (p =0.05, Chi Square Test). This large retrospective cohort study demonstrates that FL harboring combined overexpression of Bcl-2 and SOCS3 was associated with an approximately 50% reduction in survival from the time of diagnosis as compared to subjects with FL marked by overexpression of Bcl-2 alone. This effect was independent of the FLIPI score. These findings suggest that overexpression of SOCS3 protein may be a poor prognostic factor in patients with de novo FL. Further studies will examine whether combined overexpression of Bcl-2 and SOCS3 results in deregulation of cellular pathways which portend a more aggressive natural history of follicular lymphoma.