Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia

BCL-6 mutations are accumulated during B-cell transit through the germinal center (GC) and provide a histogenetic marker for B-cell tumors. On the bas is of a comprehensive analysis of 308 B-cell neoplasms, we (1) expand the s pectrum of tumors associated with BCL-6 mutations; (2) corroborate the noti on that mutations cluster with GC and post-GC B-cell neoplasms; and (3) ide ntify heterogeneous mutation frequency among B-lineage diffuse large cell l ymphoma (B-DLCL) subsets. Mutations are virtually absent in acute lymphobla stic leukemia (P<.001) and mantle cell lymphoma (P <.05), whereas they occu r frequently in GC or post-GC neoplasms, including lymphoplasmacytoid lymph oma, follicular lymphoma, MALT lymphomas, B-DLCL and Burkitt lymphoma. Amon g B-DLCL, mutations occur frequently in systemic nodal B-DLCL, primary extr anodal B-DLCL, CD5(+) B-DLCL, CD30(+) B-DLCL, and primary splenic B-DLCL, s uggesting a similar histogenesis of these B-DLCL subsets, Conversely, mutat ions are rare in primary mediastinal B-DLCL with sclerosis (10.0%; P <.01), supporting a distinct histogenesis for this lymphoma, Longitudinal follow- up of B-DLCL transformed from follicular lymphoma shows that they BCL-6 mut ations may accumulate during histologic progression, Mutations also occur i n some B-cell chronic lymphocytic leukemias, small lymphocytic lymphomas, a nd hairy cell leukemias, consistent with the hypothesis that a fraction of these lymphoproliferations are related to GC-like cells. Finally, the molec ular pattern of 193 mutational events reinforces the hypothesis that mutati ons of BCL-6 and immunoglobulin genes are caused by similar mechanisms.