Single nucleotide polymorphism‐arrays provide new insights in the pathogenesis of post‐transplant diffuse large B‐cell lymphoma

Abstract

SummaryPost-transplant lymphoproliferative disorders (PTLD) are complications of solid organ transplantation associated with severe morbidity and mortality. Diffuse large B-cell lymphoma (DLBCL) represents the most common form of monomorphic PTLD. We studied 44 cases of post-transplant DLBCL (PT-DLBCL) with high-density genome wide single nucleotide polymorphismbased arrays, and compared them with 105 cases of immunocompetent DLBCL (IC-DLBCL) and 28 cases of Human Immunodeficiency Virusassociated DLBCL (HIV-DLBCL). PT-DLBCL showed a genomic profile with specific features, although their genomic complexity was overall similar to that observed in IC-and HIV-DLBCL. Among the loci more frequently deleted in PT-DLBCL there were small interstitial deletions targeting known fragile sites, such as FRA1B, FRA2E and FRA3B. Deletions at 2p16.1 (FRA2E) were the most common lesions in PT-DLBCL, occurring at a frequency that was significantly higher than in IC-DLBCL. Genetic lesions that characterized post-germinal center IC-DLBCL were under-represented in our series of PT-DLBCL. Two other differences between IC-DLBCL and PT-DLBCL were the lack of del(13q14.3) (MIR15/MIR16) and of copy neutral LOH affecting 6p [major histocompatibility complex (MHC) locus] in the latter group. In conclusion, PT-DLBCL presented unique features when compared with IC-DLBCL. Changes in PT-DLBCL were partially different to those in HIV-DLBCL, suggesting different pathogenetic mechanisms in the two conditions linked to immunodeficiency.

Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome

“…In the immunodeficiency-related DLBCL, the presence of Epstein-Barr virus infection is associated with a lower number of genomic aberrations. 28,29 Although RS arises in the preexisting immunodeficiency associated with CLL, 1 Epstein-Barr virus infection does not play a major role in RS 2,3 and is an unlikely explanation for our data. Epigenetic changes, such as specific methylation patterns, 30 or still-unidentified somatic mutations, might explain the observed relative low genomic complexity in RS vs DLBCL.…”

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

“…Constitutional duplications in the region were also reported in 8 DECIPHER cases and 1 recently reported case (chr2:60150427-61816209, hg19) (52) that had no consistent abnormalities or evidence of a mirror image phenotype (e.g., macrocephaly). Further evidence of genomic instability in the same region exists in cancer, leading to loss, gain, or amplification of 2p15p16.1 genes in approximately 30% of cases of lymphoma (53,54). It is interesting to note that cancer-related abnormalities in the 2p15p16.1 region were reported to coincide with fragile site, aphidicolin type, common, fra(2)(p13) (or FRA2E) (55).…”

EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features

“…IG mutation analysis performed in 21 cases (including eight cases of ''early'' EBV þ PT-DLBCL developed after 1-12 months following transplantation) displayed clonal IG rearrangements in all tumors (data not shown). In this series, the most frequent graft was kidney (11/27), followed by hematopoietic stem cells (HSC) (6/27), heart (5/27), and [2],add(3)(q21) [4],þ5 [3],þdel(7)(q22) [3],add(11)(q22) [4],þ12 [3], add(13) (q34) [3],þi(15)(q10),þ16 [4],þ17 [3],þ add(17)(q25) [5],þadd(19)(q13) liver (4/27). All PT-DLBCL following HSC or heart transplantation were EBER þ .…”

“…Genetic studies have shown that PT-DLBCL share genetic aberrations with IC-DLBCL, but also present with distinct lesions (2)(3)(4). It was also suggested that EBV þ PT-DLBCLs have a less complex genomic profile compared with EBV À PT-DLBCL.…”