IIGH::NSD2/I Fusion Gene Transcript as Measurable Residual Disease Marker in Multiple Myeloma

• Published in: Cancers 2024-01, Vol.16 (2)
• Main Authors: Bors, András, Kozma, András, Tomán, Ágnes, Őrfi, Zoltán, Kondor, Nóra, Tasnády, Szabolcs, Vályi-Nagy, István, Reményi, Péter, Mikala, Gábor, Andrikovics, Hajnalka
• Format: Article
• Language: English
• Subjects: Cancer; Genes; Genetic aspects; Medical research; Medicine, Experimental; Messenger RNA; Proteins
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16020283

Multiple myeloma is the second most common malignant hematologic cancer. In approximately 15% of cases, a chromosomal abnormality, t(4;14), leads to uncontrolled production of a protein called NSD2. Different-sized fragments may be missing from the initial segment of this protein, resulting in the creation of three types of breakpoints in the gene encoding the protein. Examining the level of complex (fusion) mRNAs responsible for protein formation might be crucial in the treatment of patients, as lower levels could be associated with a more favorable survival outcome. We have developed a quantitative polymerase chain reaction system capable of detecting measurable residual disease with a sensitivity of up to 1:100,000. Our study also demonstrated that the survival of patients with different breakpoint mRNAs may vary. Among them, those with intermediate-length mRNAs have the worst outcomes. 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.