Diffuse large B-cell lymphoma (DLBCL) is characterized by deregulation of numerous signaling pathways that direct cell proliferation and survival during B-cell maturation in the germinal center reaction. The subtype of germinal center B-cell DLBCL (GCB-DLBCL) demonstrates addiction to tonic B-cell receptor (BCR) signaling in part through the PI3K-AKT pathway. However, a comprehensive catalogue of the somatic genetic alterations leading to this deregulation is currently lacking and represents a limitation in advancing precision medicine options. In this study, we present a comprehensive analysis in 347 DLBCL biopsies uniformly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), describing recurrent mutations, copy number alterations, and clinical parameters that are associated with AKT activation (pAKT) as determined by immunohistochemistry. We observed a significantly enhanced pAKT population including players in the Gα13 signaling (GNA13, P2RY8, ARHGEF1, RHOA, and S1PR2) and PI3K activation pathways (NFATC1, USP7, PTEN, INPP4B). Following this correlation, we observed a co-occurrence of BCL2 protein overexpression and mutation in Gα13 signaling associated with advanced clinical stage (P = .008) in 183 GCB-DLBCL cases, as well as activation of cell migration and cell-cell adhesion pathways, indicating their contribution to lymphoma dissemination. This co-occurrence was shown to be associated with shorter time to progression in GCB-DLBCL (P = .005). We furthermore uncovered recurrent deletions of INPP4B, a lipid phosphatase involved in AKT deactivation, to be associated with increased pAKT in GCB-DLBCL. We observed that INPP4B loss is similarly associated with shorter time to progression (P = .036) in GCB-DLBCL, and demonstrated altered AKT phosphorylation in a GCB-DLBCL-derived cell line with a monoallelic INPP4B deletion. We present here a useful comprehensive tool, through a positive correlation to enhanced pAKT staining, to uncover novel prognostic indicators related to genetic alteration status in DLBCL. Our findings provide novel insight into somatic genomic alterations underlying prosurvival signaling of GC-derived lymphomas, and present new avenues for therapeutic targeting.

Citation Format: Shannon Healy, Daisuke Ennishi, Elena Viganò, Aixiang Jiang, Anja Mottok, Stacy Hung, Olga Kutovaya, Gerben Duns, Bruce Woolcock, David Scott, Christian Steidl. Comprehensive correlation between genetic alterations in DLBCL and deregulated activation of the PI3K-AKT pathway isolates unique players in lymphoma dissemination and inferior outcome [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-18.