Hypermutation of Multiple Proto-Oncogenes in B-cell Diffuse Large-Cell Lymphomas

Nature. 2001 Jul 19;412(6844):341-6. doi: 10.1038/35085588.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • B-Lymphocytes*
  • DNA Mutational Analysis
  • DNA-Binding Proteins*
  • Genes, myc
  • Germinal Center / cytology
  • Humans
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / immunology
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / immunology
  • Molecular Sequence Data
  • Mutation*
  • PAX5 Transcription Factor
  • Proteins / genetics
  • Proto-Oncogenes*
  • Transcription Factors*

Substances

  • DNA-Binding Proteins
  • PAX5 Transcription Factor
  • PAX5 protein, human
  • Proteins
  • Transcription Factors

Associated data

  • GENBANK/AF386789
  • GENBANK/AF386790
  • GENBANK/AF386791