Abstract
Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.
Highlights
Post-transplant lymphoproliferative disorders (PTLD) encompass morphologically heterogeneous entities with variable clinical behavior. [1] PTLDs of B-lineage predominate, while T- and NK-cell PTLDs (T/ NK-PTLD) are rare, representing 2-15% of all cases. [2] T/NK-PTLDs usually present late after transplantation, are associated with a poor prognosis, and, in contrast to B-cell PTLDs, only a minority are EBV-related. [2, 3]The pathogenesis of T/NK-PTLDs and the underlying molecular alterations are presently unknown and their relationship to peripheral T-cell lymphomas (PTCL) arising in immunocompetent hosts remains unclear
Our series of T/NK-PTLD comprised a spectrum of PTCL subtypes that have been reported to occur post organ transplantation and are recognized as monomorphic PTLDs in the 2008 WHO classification [3, 4]
Epidemiologic data drawn from national registries have shown a higher frequency of PTCL, NOS, ALCL, hepatosplenic T-cell lymphoma (HSTCL), and ENKTCL in transplant recipients
Summary
Post-transplant lymphoproliferative disorders (PTLD) encompass morphologically heterogeneous entities with variable clinical behavior. [1] PTLDs of B-lineage predominate, while T- and NK-cell PTLDs (T/ NK-PTLD) are rare, representing 2-15% of all cases. [2] T/NK-PTLDs usually present late after transplantation, are associated with a poor prognosis, and, in contrast to B-cell PTLDs, only a minority are EBV-related (up to 37%). [2, 3]The pathogenesis of T/NK-PTLDs and the underlying molecular alterations are presently unknown and their relationship to peripheral T-cell lymphomas (PTCL) arising in immunocompetent hosts remains unclear. Post-transplant lymphoproliferative disorders (PTLD) encompass morphologically heterogeneous entities with variable clinical behavior. [2] T/NK-PTLDs usually present late after transplantation, are associated with a poor prognosis, and, in contrast to B-cell PTLDs, only a minority are EBV-related (up to 37%). The pathogenesis of T/NK-PTLDs and the underlying molecular alterations are presently unknown and their relationship to peripheral T-cell lymphomas (PTCL) arising in immunocompetent hosts remains unclear. In order to gain insights into the genetic bases of these uncommon PTLDs, we performed targeted generation sequencing of cancer-associated genes and genome-wide DNA profiling to assess copy number alterations in a relatively large series of well characterized T/NK-PTLDs. We observed frequent mutations of epigenetic modifiers, members of the JAK/ STAT signaling cascade, and TP53, and recurrent genomic alterations, similar to those described in PTCL arising in immunocompetent individuals. Immunosuppression; MSI: Microsatellite instability; TCR: T-cell receptor clonality; CM: Cardiomyopathy; CHD: Congestive heart failure; GN: Glomerulonephritis; DM: Diabetes Mellitus; FSGS: Focal segmental glomerulosclerosis; APCKD: Autosomal dominant polycystic kidney disease; LN: Lymph node; BM: Bone marrow; AZA: Azathioprine; CS: Corticosteroids; P: Prednisone; CNI: Calcineurin inhibitor; MMF: Mycophenolate mofetil; RT: Radiotherapy; N/A: Not available; ND: Not done; PC: Polyclonal; * EBER+ B-cells were present
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