Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas.
Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.
Pasqualucci
L
L
Institute for Cancer Genetics and the Department of Pathology, Columbia University, New York, New York 10032, USA.
Neumeister
P
P
Goossens
T
T
Nanjangud
G
G
Chaganti
R S
RS
Küppers
R
R
Dalla-Favera
R
R
D001402:B-Lymphocytes; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D016259:Genes, myc; D018858:Germinal Center / Q000166:cytology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D051757:PAX5 Transcription Factor; D011506:Proteins / Q000235:genetics; D011519:Proto-Oncogenes; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D011506:Proteins; D014157:Transcription Factors