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 basis of a comprehensive analysis of 308 B-cell neoplasms, we (1) expand the spectrum of tumors associated with BCL-6 mutations; (2) corroborate the notion that mutations cluster with GC and post-GC B-cell neoplasms; and (3) identify heterogeneous mutation frequency among B-lineage diffuse large cell lymphoma (B-DLCL) subsets. Mutations are virtually absent in acute lymphoblastic leukemia (P <.001) and mantle cell lymphoma (P <.05), whereas they occur frequently in GC or post-GC neoplasms, including lymphoplasmacytoid lymphoma, follicular lymphoma, MALT lymphomas, B-DLCL and Burkitt lymphoma. Among B-DLCL, mutations occur frequently in systemic nodal B-DLCL, primary extranodal B-DLCL, CD5(+) B-DLCL, CD30(+) B-DLCL, and primary splenic B-DLCL, suggesting a similar histogenesis of these B-DLCL subsets. Conversely, mutations 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 mutations may accumulate during histologic progression. Mutations also occur in some B-cell chronic lymphocytic leukemias, small lymphocytic lymphomas, and hairy cell leukemias, consistent with the hypothesis that a fraction of these lymphoproliferations are related to GC-like cells. Finally, the molecular pattern of 193 mutational events reinforces the hypothesis that mutations of BCL-6 and immunoglobulin genes are caused by similar mechanisms. (Blood. 2000;95:651-659)
Capello
D
D
Divisions of Internal Medicine and Epidemiology, Department of Medical Sciences, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Vitolo
U
U
Pasqualucci
L
L
Quattrone
S
S
Migliaretti
G
G
Fassone
L
L
Ariatti
C
C
Vivenza
D
D
Gloghini
A
A
Pastore
C
C
Lanza
C
C
Nomdedeu
J
J
Botto
B
B
Freilone
R
R
Buonaiuto
D
D
Zagonel
V
V
Gallo
E
E
Palestro
G
G
Saglio
G
G
Dalla-Favera
R
R
Carbone
A
A
Gaidano
G
G
D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D011519:Proto-Oncogenes; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors