CAT #: IGH-Somatic-Hypermutation-Assay

IGH Somatic Hypermutation Assay

  • Description of Test:

    For detection of the vast majority of clonal IGH VH-JH rearrangements, including the associated VH-JH region DNA sequences, a multiplex master mix targeting the conserved framework region 1 (FR1) or leader and the joining region is used for PCR amplification.  Next-generation sequencing of the PCR products is used to identify the frequency distribution of VH region and JH region segment utilization, as well as for the definition of the extent of somatic hypermutation present in the IGH gene.  Bioinformatics tools facilitate the characterization of sequences present at greater than 2.5% of the population and the level of somatic hypermutation present in the dominant clone.  Bioinformatics also identify clonal rearrangements that involve the V3-21 gene, which has been associated with a poor prognosis in CLL, independent of SHM status.

  • Overview:

    Lymphoid cells are different from the other somatic cells in the body as during development, the antigen receptor genes in these cells undergo somatic gene rearrangement.1  During B-cell development, genes encoding the human immunoglobulin heavy chain (IGH) proteins are assembled from multiple polymorphic gene segments that undergo rearrangements and selection, generating VH-DH-JH combinations that are unique in both length and sequence for each cell.2,3  An additional level of diversity is generated by point mutations in the variable regions, also known as somatic hypermutations (SHM).

    Leukemias and lymphomas originate from the malignant transformation of individual lymphoid cells, which means that all leukemias and lymphomas generally share one or more cell-specific or “clonal” antigen receptor gene rearrangements.  Therefore, tests that detect IGH clonal rearrangements can be useful in the study of B-cell malignancies.

    Immunoglobulin variable heavy chain gene hypermutation status provides important prognostic information for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).  The presence of IGH SHM is defined as greater or equal to 2% difference from the germline VH gene sequence, whereas less than 2% difference is considered evidence of no SHM.  The status of SHM for clone(s) has clinical relevance, as there is a clear distinction in the median survival of patients with and without SHM.  Hypermutation of the IGH variable region is strongly predictive of a good prognosis, while lack of mutation predicts a poor prognosis.4  In addition, this assay identifies clonal rearrangements involving the V3-21 gene, which has been associated with a poor prognosis in CLL independent of SHM status.  This assay has been shown to further stratify CLL patients.5

Service Details

  • Indications for Testing:
    • Identify clonality in atypical lymphoproliferative disorders
    • Support a differential diagnosis between reactive lesions and hematologic malignancies
    • Assign presumptive lineage in mature monoclonal lymphoproliferative disorders
    • Monitor and evaluate disease recurrence
  • Service Description:

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References

  1. Tonegawa, S (1983) Nature. 302:575-581.
  2. Trainor, KJ et al. (1990) Blood. 75:2220-222 2.
  3. Miller, JE et al. (2013, 2nd ed.) Springer Science & Business Media.2.7.13 and 30.2.7.18.
  4. Ghia, P et al. (2007) Leukemia. 21:1-3.
  5. Stamatopoulos, B et al. (2017) Leukemia. 31(4):837-845.

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