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

Author

Listed:
  • Laura Pasqualucci

    (Columbia University)

  • Peter Neumeister

    (Columbia University)

  • Tina Goossens

    (Institute for Genetics, University of Cologne)

  • Gouri Nanjangud

    (Memorial Sloan-Kettering Cancer Center)

  • R. S. K. Chaganti

    (Memorial Sloan-Kettering Cancer Center)

  • Ralf Küppers

    (Columbia University
    Institute for Genetics, University of Cologne)

  • Riccardo Dalla-Favera

    (Columbia University)

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.

Suggested Citation

  • Laura Pasqualucci & Peter Neumeister & Tina Goossens & Gouri Nanjangud & R. S. K. Chaganti & Ralf Küppers & Riccardo Dalla-Favera, 2001. "Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas," Nature, Nature, vol. 412(6844), pages 341-346, July.
  • Handle: RePEc:nat:nature:v:412:y:2001:i:6844:d:10.1038_35085588
    DOI: 10.1038/35085588
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    Cited by:

    1. Nikolai Schleussner & Pierre Cauchy & Vedran Franke & Maciej Giefing & Oriol Fornes & Naveen Vankadari & Salam A. Assi & Mariantonia Costanza & Marc A. Weniger & Altuna Akalin & Ioannis Anagnostopoulo, 2023. "Transcriptional reprogramming by mutated IRF4 in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Martin Boström & Erik Larsson, 2022. "Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    3. Daniel Malzl & Mihaela Peycheva & Ali Rahjouei & Stefano Gnan & Kyle N. Klein & Mariia Nazarova & Ursula E. Schoeberl & David M. Gilbert & Sara C. B. Buonomo & Michela Virgilio & Tobias Neumann & Rush, 2023. "RIF1 regulates early replication timing in murine B cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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