From the Guidelines
Somatic hypermutation (SHM) lab testing is primarily used to assess B-cell lymphoproliferative disorders, particularly in diagnosing and managing chronic lymphocytic leukemia (CLL), where it helps determine the prognosis and guides treatment decisions. This test analyzes the pattern of mutations in the variable regions of immunoglobulin genes within B cells, which is crucial for identifying clonal B-cell populations and distinguishing between reactive and malignant B-cell populations 1. The results of SHM analysis can provide valuable prognostic information, helping to predict the likelihood of disease progression and the need for treatment in patients with CLL.
Key aspects of SHM lab testing include:
- Analyzing the pattern of mutations in immunoglobulin genes to determine the clonality of B-cell populations
- Distinguishing between reactive and malignant B-cell populations
- Providing prognostic information to guide treatment decisions in CLL and other B-cell lymphoproliferative disorders
- Requiring specialized molecular techniques, including PCR amplification and DNA sequencing of immunoglobulin gene segments, typically performed on blood, bone marrow, or tissue samples 1.
In the context of CLL, SHM status is a critical biomarker for assessing prognosis, with patients having unmutated IGHV genes (U-CLL) typically experiencing a more aggressive disease course than those with mutated IGHV genes (M-CLL) 1. The European Research Initiative on CLL (ERIC) has provided recommendations for the analysis and interpretation of SHM status in CLL, emphasizing the importance of accurate and reliable testing methods 1.
While SHM lab testing is a valuable tool in the diagnosis and management of B-cell lymphoproliferative disorders, it is essential to consider the results in the context of other clinical and laboratory findings to ensure accurate diagnosis and effective treatment planning.
From the Research
Somatic Hypermutation Lab Test
A somatic hypermutation (SHM) lab test is drawn for several purposes, including:
- Determining the prognosis of chronic lymphocytic leukemia (CLL) patients, as SHM status is an important prognostic indicator for CLL 2, 3
- Identifying clonal immunoglobulin gene rearrangements in neoplastic B-cell populations 2
- Monitoring minimal residual disease (MRD) in CLL patients 2
- Detecting prognostically important CLL single nucleotide variants, insertions/deletions, and copy number variants 3
- Studying the role of aberrant SHM in lymphoma, particularly in diffuse large B-cell lymphoma (DLBCL) 4
- Analyzing stereotyped patterns of SHM in subsets of CLL patients, which may imply the role of antigen selection in leukemogenesis 5
Key Applications of SHM Lab Test
The SHM lab test has several key applications, including:
- Evaluation of SHM status in CLL patients using next-generation sequencing (NGS) 2, 3
- Detection of IGHV somatic hypermutation in CLL patients using targeted capture NGS 3
- Identification of recurrent targets of aberrant SHM in lymphoma 4
- Analysis of SHM patterns in CLL subsets defined by IGHV gene usage, stereotyped HCDR3 sequences, and mutational load 5
Underlying Mechanisms of SHM
The SHM process involves:
- Double-strand DNA breaks, activation-induced cytidine deaminase (AID), and error-prone DNA repair 6
- The expression of AID, which is selectively expressed upon CD40-signaling in hypermutating B cells 6
- The modulation of critical translesion DNA polymerases, which leads to the insertions of mismatches, i.e., mutations 6