[User Story] Add IGHV mutation analysis #1572
Description
Need
As a clinician interpreting lymphomas and chronic lymphocytic leukemia I would like to know the mutation status of IGHV (immunoglobulin heavy chain variable region). This analysis will be validated for the lymphoid panel but we do according to some research users not have a good analysis for this at the moment, TNscope and VarDict are not optimal. These research users have instead used this tool for the purpose: https://github.com/ferrannadeu/IgCaller
Suggested approach
NOT SURE YET BUT...
The results from this analysis sounds like something you want a report about, or a type of "status", not something you want to piece together yourself by looking at a general table of somatic SNVs.
Probably we can add an analysis for this for all our workflows, but only show a report if we have information from the region. (some panels will not include the region)
Considered alternatives
No response
Deviation
No response
System requirements assessed
- Yes, I have reviewed the system requirements
Requirements affected by this story
No response
Risk assessment needed
- Needed
- Not needed
Risk assessment
No response
SOUPs
No response
Can be closed when
No response
Blockers
No response
Anything else?
Information from ChatGPT about the analysis:
Immunoglobulin (IG) genes are a group of genes that encode antibodies, or immunoglobulins, which are essential components of the adaptive immune system. These genes undergo a process called V(D)J recombination, where variable (V), diversity (D), and joining (J) gene segments rearrange to generate the diverse antibody repertoire needed to recognize a wide array of antigens.
1. IG Genes Overview
There are three main IG loci in humans:
- IGH (Immunoglobulin Heavy Chain)
- IGK (Immunoglobulin Kappa Light Chain)
- IGL (Immunoglobulin Lambda Light Chain)
In particular, the IGHV (Immunoglobulin Heavy Chain Variable region) genes are a focus in mutation analysis.
2. What is IGHV Mutation Analysis?
IGHV mutation analysis refers to sequencing and comparing the IGHV region of a B-cell’s immunoglobulin gene to the corresponding germline (unaltered) IGHV gene sequence. The goal is to determine whether the sequence has undergone somatic hypermutation (SHM) — a normal process in which B cells mutate their antibody genes to increase antibody affinity during an immune response.
- If the IGHV region is ≥98% identical to germline, it is considered unmutated.
- If the IGHV region is <98% identical to germline, it is considered mutated.
3. Why Is IGHV Mutation Analysis Important?
It is particularly critical in chronic lymphocytic leukemia (CLL), and also has relevance in some lymphomas. The mutation status of IGHV has prognostic and therapeutic implications.
In CLL:
- Unmutated IGHV is associated with:
- More aggressive disease
- Shorter time to first treatment
- Poorer overall survival
- Mutated IGHV correlates with:
- Indolent disease course
- Better prognosis
- Good response to certain therapies
In Follicular lymphoma (FL) and mantle cell lymphoma (MCL):
- IGHV gene usage and somatic mutation status can also be studied for disease classification and origin (e.g., germinal center vs non-germinal center derivation), though the clinical utility isn't as well-established as in CLL.
4. Clinical Applications
- Risk stratification in CLL: Helps guide whether early treatment is warranted.
- Treatment decisions: Some newer therapies (e.g., BTK inhibitors) are effective regardless of IGHV status, while others (e.g., chemoimmunotherapy like FCR: fludarabine, cyclophosphamide, rituximab) are more beneficial in mutated IGHV patients.
- MRD (Minimal Residual Disease) tracking: IGHV rearrangements can also serve as clonal markers for detecting residual disease.
Would you like to see an example IGHV mutation analysis report or how sequencing data is used to determine mutation status?