Abstract
Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair1. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression2, 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 cells3. 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 breaks4,5,6. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.
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Acknowledgements
We thank V. Miljkovic and A.-M. Babiac for assistance in DNA sequencing; C. Göttlinger for help with the single-cell sorting; M. Introna for providing the sequence of the A-MYB gene, and B. Jungnickel for providing DNA from sorted human naive and germinal-centre B-cell populations. We are grateful to U. Klein for discussions and to R. Baer for critically reading the manuscript. L.P. was a Fellow of the American Italian Cancer Foundation. P.N. was supported by the Max Kade Foundation. This work was supported by grants from the National Institute of Health to R.D.-F. and R.S.K.C., and from the Deutsche Forschungsgemeinschaft and a Heisenberg Award to R.K.
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Pasqualucci, L., Neumeister, P., Goossens, T. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001). https://doi.org/10.1038/35085588
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DOI: https://doi.org/10.1038/35085588
