IGHV gene mutational analysis in CLL

(contact persons: Dr. Paolo Ghia, Milan/Italy; Dr. Richard Rosenquist, Uppsala/Sweden)

Determination of the mutational status of rearranged immunoglobulin heavy chain variable (IGHV) genes in patients with CLL has proved to be one of the most important prognostic factors and it is now widely used to stratify patients in clinical trials. For this reason, consensus procedures for performing and interpreting IGHV mutational analysis in CLL are strongly needed to set standards which may allow direct comparison of IGHV sequence data between laboratories, as in new multicenter treatment trials.

ERIC consensus recommendations for a reliable analysis

Given the importance of this analysis, as part of ERIC activities, several investigators involved in CLL clinical research from different European countries, discussed the current and most updated literature as well as their own laboratory experience and reached a consensus on this issue, taking into account all pros and cons of several technical aspects. This effort has produced recommendations on the minimum requirements for a reliable and reproducible analysis of the rearranged IGHV sequences in CLL, which are published in
Leukemia, 2007 Jan;21(1):1-3 .

These recommendations were the subject of the first two editions of the "Educational workshop on Immunoglobulin Gene Analysis in Chronic Lymphocytic Leukemia" held in Uppsala (June 2007) and Paris (October 2008). The 3rd edition of the Educational Workshop will take place in Thessaloniki on 24-25 September 2009.

Nevertheless, though these recommendations can be of help in most routine situations, investigators might have still problems to analyze real-life sequences and cases still exist which are difficult to categorize ("problematic cases"). For this purpose, this ERIC project is now twofold:

  • Online support and troubleshooting for interpretation of IGHV sequences
    A review board of experts is available online to discuss general queries on IGHV gene interpretation or analyze actual IGHV sequences that can be difficult to interpret in everyone’s daily activity; to submit queries and/or sequences please go to the » submission form.

  • Collection of problematic cases and database creation
    "Problematic cases" exist that defy a clear-cut classification and include those showing any of the following features:

    • Double in-frame rearrangements

    • Double in-frame rearrangements with discordant mutation status

    • Unmutated in-frame rearrangement coexisting with a mutated out-of-frame rearrangement

    • Unmutated heavy chain rearrangement associated with a mutated light chain rearrangement

    • Single transcribed out-of-frame rearrangements

    • Single transcribed rearrangements carrying stop codons

    • Rearrangements carrying any kind of deletions or insertions/duplications

    • In-frame rearrangements carrying a mutation either at IMGT codon C-104 (end of HFR3) or at W-118 (start of HFR4)

    • Rearrangements without a clearly defined junction

    Though these cases are probably known to anyone working in IGHV analysis in CLL, they are limited in frequency, hampering a meaningful analysis at a single-institution level. Therefore, we propose to collect in a dedicated database all problematic cases in order to reach a significant number of them. Everyone in the CLL community is welcome to participate to this joint effort; to submit problematic IGHV sequences and participate to the project please go to the » submission form

 

Review Board
Chrysoula Belessi, Athens/Greece
Frederic Davi, Paris/France
Paolo Ghia, Milan/Italy
Anton Langerak, Rotterdam/The Netherlands
Kathy Potter, Southampton/UK
Richard Rosenquist, Uppsala/Sweden
Kostas Stamatopoulos, Thessaloniki/Greece

 

USEFUL LINKS for Immunoglobulin genes analysis

New IMGT/V-Quest search page
Link opens new window http://imgt.cines.fr/IMGT_vquest/share/textes/index.html

The IgBLAST webpage at NCBI
Link opens new window http://www.ncbi.nlm.nih.gov/igblast

VBase/DNAPlot website
Link opens new window  http://vbase.mrc-cpe.cam.ac.uk

The JoinSolver® website
Link opens new window http://joinsolver.niams.nih.gov/index.htm

SoDa Dulci website
Link opens new window http://dulci.biostat.duke.edu/soda