title: Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology.
abstract: B-cell post-transplant lymphoproliferative disorders (PTLD) are classified as early lesions, polymorphic lymphomas (P-PTLD) and monomorphic lymphomas (M-PTLD). These morphologic categories are thought to reflect a biologic continuum, although supporting genetic data are lacking. To gain better insights into PTLD pathogenesis, we characterized the phenotypes, immunoglobulin (Ig) gene alterations and non-Ig gene (BCL6, RhoH/TTF, c-MYC, PAX5, CIITA, BCL7A, PIM1) mutations of 21 PTLD, including an IM-like lesion, 8 P-PTLD and 12 M-PTLD. Gene expression profile analysis was also performed in 12 cases. All PTLD with clonal Ig rearrangements showed evidence of germinal centre (GC) transit based on the analysis of Ig and BCL6 gene mutations, and 74% had a non-GC phenotype (BCL6 +/- MUM1+). Although surface Ig abnormalities were seen in 6/19 (32%) PTLD, only three showed 'crippling' Ig mutations indicating other etiologies for loss of the B-cell receptor. Aberrant somatic hypermutation (ASHM) was almost exclusively observed in M-PTLD (8/12 vs. 1/8 P-PTLD) and all three recurrent cases analysed showed additional mutations in genes targeted by ASHM. Gene expression analysis showed distinct clustering of PTLD compared to B-cell non-Hodgkin lymphomas (B-NHL) without segregation of P-PTLD from non-GC M-PTLD or EBV+ from EBV- PTLD. The gene expression pattern of PTLD appeared more related to that of memory and activated B-cells. Together, our results suggest that PTLD represent a distinct type of B-NHL deriving from an antigen experienced B-cell, whose evolution is associated with accrual of genetic lesions.
authors.affiliation: Department of Pathology, Columbia University, New York, NY 10032, USA.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
authors.forename: Mahesh M
authors.initials: MM
authors.lastname: Mansukhani
authors.forename: Gopeshwar
authors.initials: G
authors.lastname: Narayan
authors.forename: Paula M
authors.initials: PM
authors.lastname: Smith
authors.forename: Vundavalli V
authors.initials: VV
authors.lastname: Murty
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007150:Immunohistochemistry; D008232:Lymphoproliferative Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011183:Postoperative Complications; D014180:Transplantation / Q000009:adverse effects*
chemical_list: D007135:Immunoglobulin Variable Region