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Immunobiology

Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma

Leukemia volume 15, pages 1772–1778 (2001)Cite this article

Abstract

In this study, we analyzed the targeting of the somatic hypermutation (SHM) mechanism at specific hotspot sequence motifs in the VH and Vκ genes of 10 follicular lymphoma (FL) cases and the Vκ and Vλ genes of 11 κ- and six λ-light chain expressing multiple myeloma (MM) cases. These sequences were analyzed for targeting of specific motifs, ie certain highly mutable trinucleotides (3-NTPs), the tetranucleotide (4-NTP) RGYW and its complementary, WRCY (where R = purine, Y = pyrimidine and W = A or T). Comparisons were carried out between mutation frequencies in RGYW vs WRCY and the incidence of mutations in complementarity determining region (CDR)-1 vs CDR2 vs CDR3. Statistically significant differences were obtained when comparing: (1) the ratio of mutations in 4-NTPs (RGYW, WRCY, RGYW+WRCY)/mutations in the whole V sequence in MM-Vκ vs MM-Vλ; (2) the total number of mutated 4-NTPs in MM-Vκ vsFL-Vκ; (3) the number of mutated RGYW 4-NTPs in MM-Vκ vsFL-Vκ and FL-VH vs FL-Vκ; (4) the number of mutated WRCY 4-NTPs in MM-Vκ vs FL-Vκ (P = 0.006) and FL-VH vs FL-Vκ; (5) the targeting of RGYW vs WRCY in the CDRs of FL-VH genes. Similar results (regarding statistical significance) were obtained when undertaking intergroup comparisons for 3-NTPs. These findings conform well with relevant data derived from normal peripheral B cells. The differences observed in favor of 4-NTP (RGYW and WRCY) targeting in FL-VH vsFL-Vκ and MM-Vκ vs FL-Vκ may implicate differences in the evolution of SHM coupled with selection in different stages of B cell ontogeny. Several explanations can be offered for the fact that hotspot sequences were not always targeted by SHM in FL and MM: (1) other unrecognized motifs may be targets of SHM; (2) ‘inappropriately’ introduced mutations were fixed and propagated by the neoplastic process; (3) certain FL and MM cases might have lost their ability to correct mutations introduced in classic hotspots due to deficient mismatch-repair (MMR) mechanisms; conversely, in other cases with intact MMR function, the hotspot to non-hotspot targeting of somatic hypermutation is balanced.

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Authors and Affiliations

  1. Hematology Laboratory, General Hospital of Nikea, Piraeus, Greece

    C Belessi

  2. First Department of Medicine, Athens University School of Medicine, Laikon General Hospital, Athens, Greece

    K Stamatopoulos, N Stavroyianni & K Zoi

  3. Hemopathology Unit, Evangelismos Hospital, Athens, Greece

    T Papadaki

  4. Department of Medicine, Helena Venizelou Hospital, Athens, Greece

    C Kosmas

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  1. C Belessi
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Belessi, C., Stamatopoulos, K., Stavroyianni, N. et al. Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma. Leukemia 15, 1772–1778 (2001). https://doi.org/10.1038/sj.leu.2402258

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