MUTATIONAL HOT-SPOTS WITHIN THE CARBOXY-TERMINAL REGION OF THE LMP1 ONCOGENE OF EPSTEIN-BARR-VIRUS ARE FREQUENT IN LYMPHOPROLIFERATIVE DISORDERS

We have recently identified in Epstein-Barr virus (EBV) positive Hodgk in's disease (HD) a variant of the latent membrane protein 1 (LMP1) on cogene characterized by four point mutations and a 30 base pair deleti on. These findings led us to test whether such mutants were also prese nt in other lymphoproliferative disorders (LPD). We analysed 98 EBV DN A positive cases (67 LPD, 15 benign conditions, 16 lymphoblastoid cell lines) by PCR for deletions within the LMP1 gene. DNA sequencing of t he region coding for the carboxy terminal protein domain was performed on 24 cases. In 13 cases the same combination of 4 point mutations at positions 168 320, 168 308, 168 295 and 168 225 was identified. Of th ese cases, 12 had an additional point mutation at position 168 357 and eight at position 168 355, and nine had a 30 base pair deletion inclu ding nucleotides 168 285 to 168 256. These deletion mutants were ident ified in HD, angioimmunoblastic lymphadenopathy, B-immunoblastic lymph oma, peripheral T-cell lymphoma, and two lymphoblastoid cell lines. Ou r findings reveal a high frequency of non-random point mutations at pr eferential sites within the 3' (carboxy terminal) region of the LMP1 o ncogene. The association of these mutational hot spots with LPD sugges ts that they are involved in EBV related lymphomagenesis and that they define a clinically relevant EBV strain.