Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas

Genomic instability promotes tumorigenesis and can occur through various me chanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair(1). Although B-cell lymphomas are associated with chro mosomal translocations that deregulate oncogene expression(2), 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(3). Here we re port that an aberrant hypermutation activity targets multiple loci, includi ng 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 g erminal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share featur es typical of V-region-associated somatic hypermutation. In contrast to mut ations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, sugg esting 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(4-6). By mutating multiple gene s, and possibly by favouring chromosomal translocations, aberrant hypermuta tion may represent the major contributor to lymphomagenesis.