Insights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas.
Clonally related composite lymphomas of Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL) represent models to study the multistep transformation process in tumorigenesis and the development of two distinct tumors from a shared precursor. We analyzed six such lymphomas for transforming events. The HLs were combined in two cases with follicular lymphoma (FL), and in one case each with B-cell chronic lymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). In the HL/FL and HL/MCL combinations, BCL2/IGH and CCND1/IGH translocations, respectively, were detected in both the HL and NHL. No mutations were found in the tumor suppressor genes FAS, NFKBIA and ATM. The HL/DLBCL case harbored clonal replacement mutations of the TP53 gene on both alleles exclusively in the DLBCL. In conclusion, we present the first examples of molecularly verified IgH-associated translocations in HL, which also show that BCL2/IGH or CCND1/IGH translocations can represent early steps in the pathogenesis of composite HL/FL or HL/MCL. The restriction of the TP53 mutations to the DLBCL in the HL/DLBCL case exemplifies a late transforming event that presumably happened in the germinal center and affected the fate of a common lymphoma precursor cell towards development of a DLBCL.
Schmitz
R
R
Institute for Cell Biology (Tumor Research), University of Duisburg-Essen Medical School, Essen, Germany. roland.schmitz@uni-essen.de
Renné
C
C
Rosenquist
R
R
Tinguely
M
M
Distler
V
V
Menestrina
F
F
Lestani
M
M
Stankovic
T
T
Austen
B
B
Bräuninger
A
A
Hansmann
M-L
ML
Küppers
R
R
D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002999:Clone Cells; D019938:Cyclin D1 / Q000235:genetics; D016147:Genes, Tumor Suppressor; D019254:Genes, bcl-2; D006689:Hodgkin Disease / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008223:Lymphoma / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology; D009154:Mutation; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D007143:Immunoglobulin Heavy Chains; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1