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Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia

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Abstract

Νext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.

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Acknowledgments

This work was supported in part by the ENosAI project (code 09SYN-13-880) co-funded by the EU and the Hellenic General Secretariat for Research and Technology, the KRIPIS action funded by the Hellenic General Secretariat for Research and Technology, VaVPI project CEITEC CZ.1.05/1.1.00/02.0068 IGA-MZ-CR project IGA-MZ-CR NT13493-4/2012, and the National Institutes of Health grant CA136591 (awarded to D.F.J.). AA is recipient of a fellowship by Associazione Italiana per la Ricerca sul Cancro AIRC (Triennial fellowship “Guglielmina Lucatello é Gino Mazzega”).

Conflict of interest

The authors have no relevant conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece

    Aliki Xochelli, Evangelia Minga, Ioanna Chouvarda, Nikos Maglaveras, Anastasia Hadzidimitriou & Kostas Stamatopoulos

  2. Unit of B Cell Neoplasia, Division of Molecular Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Andreas Agathangelidis & Paolo Ghia

  3. Department of Informatics, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Ioannis Kavakiotis & Ioannis Vlahavas

  4. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Lesley Ann Sutton, Panagiotis Baliakas, Richard Rosenquist, Anastasia Hadzidimitriou & Kostas Stamatopoulos

  5. Lab of Medical Informatics, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Ioanna Chouvarda & Nikos Maglaveras

  6. The International ImMunoGeneTics Information System (IMGT), LIGM, Institut de Génétique Humaine IGH, Université Montpellier 2, Montpellier, France

    Véronique Giudicelli & Marie-Paule Lefranc

  7. Center for Experimental Research and Medical Studies, S. Giovanni Battista Hospital, Turin, Italy

    Lisa Bonello

  8. Department of Medicine, Hematology and Clinical Immunology Branch, School of Medicine, Padua University, Padova, Italy

    Livio Trentin

  9. Department of Oncology/Haematology, Division of Haematology, Niguarda Ca’ Granda Hospital, Milan, Italy

    Alessandra Tedeschi

  10. First Department of Propaedeutic Medicine, University of Athens, Athens, Greece

    Panagiotis Panagiotidis

  11. Department of Hematology and Pathology, Rigshospitalet, Copenhagen, Denmark

    Christian Geisler

  12. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands

    Anton W. Langerak

  13. Central European Institute of Technology, Masaryk University, Brno, Czech Republic

    Sarka Pospisilova & Nikos Darzentas

  14. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Diane F. Jelinek

  15. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    David Oscier

  16. Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA

    Nicholas Chiorazzi

  17. Hematology Department and University Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France

    Fred Davi

  18. Università Vita-Salute San Raffaele, Milan, Italy

    Paolo Ghia

  19. Hematology Department, Nikea General Hospital, Piraeus, Greece

    Chrysoula Belessi

  20. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

    Kostas Stamatopoulos

Authors
  1. Aliki Xochelli
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  2. Andreas Agathangelidis
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  3. Ioannis Kavakiotis
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  4. Evangelia Minga
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  5. Lesley Ann Sutton
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  6. Panagiotis Baliakas
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  7. Ioanna Chouvarda
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  8. Véronique Giudicelli
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  9. Ioannis Vlahavas
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  10. Nikos Maglaveras
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  11. Lisa Bonello
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  12. Livio Trentin
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  13. Alessandra Tedeschi
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  14. Panagiotis Panagiotidis
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  15. Christian Geisler
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  16. Anton W. Langerak
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  17. Sarka Pospisilova
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  18. Diane F. Jelinek
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  19. David Oscier
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  20. Nicholas Chiorazzi
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  21. Nikos Darzentas
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  22. Fred Davi
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  23. Paolo Ghia
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  24. Richard Rosenquist
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  25. Anastasia Hadzidimitriou
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  26. Chrysoula Belessi
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  27. Marie-Paule Lefranc
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  28. Kostas Stamatopoulos
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Corresponding author

Correspondence to Kostas Stamatopoulos.

Additional information

Aliki Xochelli and Andreas Agathangelidis are co-first authors.

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Xochelli, A., Agathangelidis, A., Kavakiotis, I. et al. Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia. Immunogenetics 67, 61–66 (2015). https://doi.org/10.1007/s00251-014-0812-3

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  • DOI: https://doi.org/10.1007/s00251-014-0812-3

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