title: Molecular epidemiology of EBNA-1 substrains of Epstein-Barr virus in posttransplant lymphoproliferative disorders which have infrequent p53 mutations.
abstract: Posttransplant lymphoproliferative disorders (PTLDs), which are highly associated with Epstein-Barr virus infection, have a low frequency of molecular genetic abnormalities. Recently it has been suggested certain EBV substrains may be associated with specific lymphoma subtypes. The goals of our study were two fold: 1) to determine the prevalence of EBNA-1 substrains and prognostic utility in PTLD and 2) to determine the incidence of p53 gene mutations and p53 protein overexpression in 32 EBV-positive PTLD cases. Tumor DNA was sequenced to identify EBNA-1 substrains at codon 487 and p53 gene mutations in exons 5-8. The PTLD samples contained the following EBNA-1 substrains: P-thr in 17/32 (53%), P-ala in 11/32 (34%), and V-leu in 4/32 (13%). More heterogeneity within major subtypes was seen in the PTLD cases than in the referral group. A second group of 25 referral (non-PTLD) samples including infectious mononucleosis (6) and sequential EBV positive virology samples (19) contained P-thr in 17/25 (68%); P-ala in 2/25 (8%); and V-leu in 6/25 (24%). In the 29 B-cell PTLD the time to presentation was an average of 13.3 months in the P-ala group, 16.6 months in the P-thr group, and 40.6 months in the V-leu group: (p>0.05). There was no difference in survival in patients (median overall--60 months) between the three different substrains of EBNA-1 (Log rank test, p=0.39). One of 31 (4.1%) cases (a diffuse large cell B-cell) had a p53 mutation. Seven of 31 (23%) cases (all B-cell), including the p53 mutated case, had over-expression of p53 protein. We conclude EBNA-1 substrains vary in PTLD and suggest the pattern reflects the geographical incidence of substrains in the region. We also conclude p53 mutations are not a significant molecular genetic abnormality in PTLD.
authors.affiliation: Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha 68198-3135, USA. TGREINER@UNMC.EDU
authors.forename: T C
authors.initials: TC
authors.lastname: Greiner
authors.forename: A A
authors.initials: AA
authors.lastname: Abou-Elella
authors.forename: B N
authors.initials: BN
authors.lastname: Smir
authors.forename: A
authors.initials: A
authors.lastname: Orazi
authors.forename: S
authors.initials: S
authors.lastname: Hinrichs
authors.forename: J
authors.initials: J
authors.lastname: Anderson
authors.forename: T
authors.initials: T
authors.lastname: Gross
authors.forename: P
authors.initials: P
authors.lastname: Bierman
authors.forename: R
authors.initials: R
authors.lastname: Hauke
mesh_terms: D020031:Epstein-Barr Virus Infections / Q000209:etiology / Q000235:genetics* / Q000821:virology*; D016158:Genes, p53; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000821:virology*; D009154:Mutation; D016377:Organ Transplantation / Q000009:adverse effects