A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma
The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly7Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly7Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We demonstrate that the RHOA mutation encoding p.Gly7Val, which was found in 53.3% (24 of 45) of the AITL cases examined, is oncogenic in nature using multiple molecular assays. Molecular modeling and docking simulations provided a structural basis for the loss of GTPase activity in the RHOA Gly7Val mutant. Our experimental data and modeling results suggest that the RHOA mutation encoding p.Gly7Val is a driver mutation in AITL. On the basis of these data and through integrated pathway analysis, we build a comprehensive signaling network for AITL oncogenesis.
Comparison of the mutation profiles in AITL, Burkitt lymphoma and DLBCL. Recurrent mutations with a frequency of >0.2 are shown. Mutation data for 18 cases of Burkitt lymphoma and 49 cases of DLBCL were collected from recent reports5–7. The bar graph on the right shows the relative ratio of mutations in the three types of lymphoma with the same color scheme.