Structural and Functional Analysis of Oncogenes and Tumor Suppressor Genes in Adult T-Cell Leukemia/Lymphoma Shows Frequent p53 Mutations

Abstract

The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing adult T-cell leukemia/lymphoma (ATLL). However, the long latency period between infection and development of ATLL, as well as the small fraction of the infected population that actually develops this disease, suggest that additional factors are involved in its pathogenesis. Therefore, we performed a molecular analysis of 10 cases of ATLL presenting in a nonendemic area that were shown to have HTLV-I sequences by polymerase chain reaction as well as clonal T-cell receptor beta gene rearrangements. We analyzed these cases for alterations in some of the oncogenes and tumor suppressor genes frequently involved in hematopoietic neoplasia. Specifically, we used a single-strand conformation polymorphism assay to determine the presence of mutations in the p53 tumor suppressor gene, as well as the K-RAS, N-RAS, H-RAS, and c-myc oncogenes. In addition, we studied the c-myc gene for rearrangements by Southern blotting and assessed expression of the retinoblastoma (Rb) and p53 genes by immunostaining. Analysis of the c-myc gene and the RAS family of oncogenes did not show any alterations. Also, the Rb gene was expressed in all cases analyzed. However, we found mutations of the p53 gene in 3 of the 10 cases and these results were confirmed by sequence analysis. In two of these cases, we showed by restriction fragment length polymorphism analysis of chromosome 17p sequences that the p53 mutations were accompanied by a loss of heterozygocity. Also, these mutations correlated with an altered pattern of p53 expression. Thus, mutations in the p53 locus may be a cofactor for the development of ATLL in some cases, whereas the c-myc, Rb, and RAS genes do not appear to be involved in these neoplasms.