SNP-Arrays Provide New Insights Into the Pathogenesis of Post-Transplant Diffuse Large B-Cell Lymphoma (PT-DLBCL).
Authors: Rinaldi Andrea , Capello Daniela , Scandurra Marta , Greiner Timothy C. , Chan Wing C. , Rossi Davide , Bhagat Govind , Paulli Marco , Inghirami Giorgio , Ponzoni Maurilio , Moreno Santiago Montes , Piris Miguel A. , Mian Michael , Rancoita Paola M.V. , Zucca Emanuele , Dalla-Favera Riccardo , Gaidano Gianluca , Kwee Ivo , Bertoni Francesco 
Published: October 2019

Abstract
Abstract 444
Post transplant lymphoproliferative disorders (PTLD) are important complications of solid organ transplantation associated with severe morbidity and mortality. DLBCL represents the most common form of monomorphic PTLD. Since knowledge of the pathogenesis of monoclonal PTLD is limited, we studied a series 44 cases of PT-DLBCL with high-density genome wide SNP-based arrays, and compared them with 105 cases immunocompetent DLBCL (IC-DLBCL) and 28 cases of HIV-DLBCL. Methods. DNA was extracted from frozen biopsies. All 177 DNA profiles were obtained using the Affymetrix GeneChip Human Mapping 250K NspI arrays. Recurrent minimal common regions (MCR) were defined using the algorithm by Lenz et al. (PNAS, 2008). Differences in frequencies between subgroups were evaluated using Fisher's exact test followed by multiple test correction. Results. The most common MCR were losses at 2p16.1 (29%) and 17p11.2-p13.3 (22%, TP53), and gains at 11q14.2-q24.2 (22%) and 7q (22%). Amplifications occurred in 7% at 9p23-p24 (PTPRD, JAK2, JMJD2C). MCRs more frequently deleted in PT-DLBCL when compared to IC-DLBCL included a series of small interstitial deletions at 1p32.2, 2p16.1, 3p14.2, 4p14, 14q13.2, 20p12.3, 20q13.32. Some of these aberrations targeted known fragile sites (FRA3B, FRA1B and FRA2E). FRA2E deletion showed the most significant difference with IC-DLBCL (PT-DLBCL 30% vs IC-DLBCL 4%, p<0.0001, adj.p<0.0005) and contained two genes, Vaccinia Related Kinase 2 (VRK2) and Fanconi anemia, complementation group L (FANCL). VRK2 is a negative regulator of MAPK pathway. FANCL is an E3 ubiquitin ligase, that is part of the FA nuclear protein complex, mainly involved in DNA repair, but also in telomere stability, chromatin remodelling, cell cycle regulation and apoptosis. No deletions of WW domain-containing Oxidoreductase (WWOX) were observed in PT-DLBCL, as opposed to HIV-DLBCL. Aside from the small interstitial deletions, PT-DLBCL overall showed a profile similar to IC-DLBCL, but PT-DLBCL contained no 13q14.3 deletions (0% vs 15%; p=0.003, adj.p = 0.04), which among other genes contains MIR15 and MIR16, and had fewer copy neutral LOH at 6p21.32-p21.33 (HLA-DR locus; 4% vs 24%; p=0.005, adj.p = 0.04). By immunophenotype, PT-DLBCL resembles most closely activated B cell like (ABC) / non germinal center (GC) B-cells. However, when compared with gene expression-classified ABC DLBCL, the MCRs characteristic of this subtype were under-represented in PT-DLBCL: gains of 18q (BCL2; 5% vs 32%; p=0.007, adj.p=0.07) and 3q (0% vs 32%; p=0.02; p=0.006, adj.p=0.07) and 6q losses (PRDM1 and TNFAIP3; 9% vs 23%; p=0.06, adj.p=0.3). Also, MCRs in GC such as 2p14-p16.1 (REL) gains were less common in PT-DLBCL compared to GC-DLBCL (11% vs 37%, p=0.019, adj.p = 0.13). In conclusion, PT-DLBCL shared similarities with IC-DLBCL, but presented unique features, such as the lack of copy neutral LOH at 6p (HLA-DR locus) and frequent breakage at fragile sites. The latter appeared partially different from what observed in HIV-DLBCL, suggesting different pathogenetic mechanisms in the context of the two conditions of immunodeficiency. The comparison with IC GC- and ABC-DLBCL subtypes indicated discrepancies between the PT-DLBCL phenotype and their genomic profile.

Disclosures:
No relevant conflicts of interest to declare.