Molecular Characterization of Post-Transplant Plasmablastic Lymphomas Implicates RAS, TP53, and NOTCH Mutations and MYC Deregulation in Disease Pathogenesis

Background: Plasmablastic lymphoma (PBL) is a rare subtype of aggressive B-cell non-Hodgkin lymphoma (B-NHL) that typically occurs in immunocompromised individuals, especially those with HIV infection or patients receiving immunosuppressive therapy for autoimmune diseases or organ allografts. Cytogenetic and gene expression profile analyses of PBL have provided some biological insights. However, the molecular and genetic alterations underlying PBL are not known. In this study, we assessed the pathologic features and spectrum of genetic mutations in a series of post-transplant PBL (PT-PBL) in order to identify molecular pathways potentially contributing to disease pathogenesis.

Methods: We searched our departmental archives for cases of PT-PBL diagnosed over the last 17 years. Morphologic and immunophenotypic features and results of in situ hybridization for EBV were evaluated. C-MYC translocations and copy number abnormalities were assessed by fluorescence in situ hybridization (FISH). Targeted next-generation sequencing of a large panel of cancer-associated genes was performed on DNA extracted from formalin-fixed paraffin-embedded tumor samples as well as corresponding non-tumor tissue in 8 of 9 cases. Microsatellite instability and immunoglobulin heavy chain ( IGH ) gene rearrangements were assessed using standard PCR based methodologies.

Results: Fourteen PT-PBL samples from 9 recipients of solid organ allografts (2 lung, 3 cardiac, 3 renal, and 1 combined liver and renal) were analyzed. The median time to development of PBL after transplant was 8 years (range 0.5 - 11.9 years). All occurred at extranodal sites. Eight of 9 patients developed de novo PT-PBL and one case represented transformation of a clonally-related plasmacytoma-like lesion. All cases showed plasmablastic morphology and 5 of 9 cases had a variable but small component of mature plasma cells (PBL with plasmacytic differentiation). All cases demonstrated a plasmablastic immunophenotype; 6/9 cases expressed CD138 and 6/9 expressed IgG. A minority of cases (2/9) were CD56 positive. Five of 9 cases were EBV positive. Four (44%) cases harbored MYC rearrangements, which were detected at diagnosis in 3 cases and acquired at disease recurrence in 1 case; 3 of these 4 cases were EBV negative. Gains of MYC were observed in an EBV positive case. Non-synonymous pathogenic somatic mutations were identified in 7/9 PT-PBL. Recurrent mutations of the RAS/MAP kinase pathway genes were the most frequent, being detected in 4/9 patients (3 KRAS , 1 with both NRAS and HRAS ). TP53 mutations occurred in 3/9 cases and NOTCH1 was mutated in 2/9 cases. Two of 9 cases had mutations in DNA mismatch repair genes and showed high level microsatellite instability, which was associated with a high burden of somatic mutations. No PRDM1 ( BLIMP1 ) mutations were observed.

Conclusions: The mutational profiles of PT-PBL differ from those reported for other types of aggressive B-NHL and implicate deregulation of MYC as well as genetic aberrations of the RAS/MAPK, TP53, and NOTCH signaling pathways in disease pathogenesis. Further studies are warranted to determine if the mutational spectrum of PT-PBL is similar to or distinct from that of PBL arising in the context of other diseases.