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IGH::NSD2 Fusion Gene Transcript as Measurable Residual Disease Marker in Multiple Myeloma
András Bors1, András Kozma1, Ágnes Tomán1
1Laboratory of Molecular Genetics, Central Hospital of Southern Pest-National Institute of Hematology and Infectious Disease, H-1097 Budapest, Hungary.
Abstract:
Multiple myeloma (MM) is the second most common hematological malignancy. Approximately 15% of MM patients are affected by the t(4;14) translocation resulting in the IGH::NSD2 fusion transcript. Breakage occurs in three major breakpoint regions within the NSD2 gene (MB4-1, MB4-2, and MB4-3), where MB4-1 leads to the production of full-length protein, while truncated proteins are expressed in the other two cases. Measurable residual disease (MRD) has been conclusively established as a crucial prognostic factor in MM. The IGH::NSD2 fusion transcript can serve as a sensitive MRD marker. Using bone marrow (BM) and peripheral blood (PB) samples from 111 patients, we developed a highly sensitive quantitative real-time PCR (qPCR) and digital PCR (dPCR) system capable of detecting fusion mRNAs with a sensitivity of up to 1:100,000. PB samples exhibited sensitivity three orders of magnitude lower compared to BM samples. Patients with an MB4-2 breakpoint demonstrated significantly reduced overall survival (p = 0.003). Our novel method offers a simple and sensitive means for detecting MRD in a substantial proportion of MM patients. Monitoring may be carried out even from PB samples. The literature lacks consensus regarding survival outcomes among patients with different NSD2 breakpoints. Our data align with previous findings indicating that patients with the MB4-2 breakpoint type tend to exhibit unfavorable overall survival.
Insights
A new method detects minimal residual disease (MRD) in multiple myeloma (MM) patients with the IGH::NSD2 translocation. The MB4-2 breakpoint is linked to poorer survival, highlighting its prognostic significance.
Area of Science:
- Hematological Malignancies
- Molecular Diagnostics
- Oncology
Background:
- Multiple myeloma (MM) is a significant hematological malignancy.
- The t(4;14) translocation, leading to IGH::NSD2 fusion, affects ~15% of MM patients.
- NSD2 gene breakpoints (MB4-1, MB4-2, MB4-3) influence protein expression.
Purpose of the Study:
- To develop a sensitive method for detecting IGH::NSD2 fusion transcripts for MRD monitoring in MM.
- To evaluate the prognostic value of different NSD2 breakpoints, particularly MB4-2, on patient survival.
Main Methods:
- Quantitative real-time PCR (qPCR) and digital PCR (dPCR) were developed to detect IGH::NSD2 fusion mRNA.
- Bone marrow (BM) and peripheral blood (PB) samples from 111 MM patients were analyzed.
- Sensitivity of the assay reached up to 1:100,000 for fusion mRNA detection.
Main Results:
- The developed assay demonstrated high sensitivity in detecting IGH::NSD2 fusion transcripts.
- PB samples showed lower sensitivity (three orders of magnitude) compared to BM samples.
- Patients with the MB4-2 breakpoint exhibited significantly reduced overall survival (p=0.003).
Conclusions:
- A novel, sensitive qPCR/dPCR method enables effective MRD monitoring in MM patients with IGH::NSD2 fusions.
- MRD monitoring can be performed using both BM and PB samples.
- The MB4-2 breakpoint is associated with unfavorable overall survival in MM, confirming its prognostic importance.
