Molecular epidemiology of EBNA-1 substrains of Epstein-Barr virus in posttransplant lymphoproliferative disorders which have infrequent p53 mutations

Posttransplant lymphoproliferative disorders (PTLDs), which are highly asso ciated with Epstein-Barr virus infection, have a low frequency of molecular genetic abnormalities. Recently it has been. suggested certain EBV substra ins may be associated with specific lymphoma subtypes. The goals of our stu dy were two fold: 1) to determine the prevalence of EBNA-1 substrains and p rognostic utility in PTLD and 2) to determine the incidence of p53 gene mut ations 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 m utations in exons 5-8. The PTLD samples contained the following EBNA-1 subs trains: 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 inc luding infectious mononucleosis (6) and sequential EBV positive Virology sa mples (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 i n patients (median overall - 60 months) between the three different substra ins of EBNA-1 (Log rank test, p=0.39). One of 31 (4.1%) cases (a diffuse la rge 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 conc lude EBNA-1 substrains vary in PTLD and suggest the pattern reflects the ge ographical incidence of substrains in the region. We also conclude p53 muta tions are not a significant molecular genetic abnormality in PTLD.