Identification and monitoring of Copy Number Variants (CNV) in monoclonal gammopathy

ABSTRACT

Monoclonal gammopathy of undetermined significance (MGUS) represents the pre-clinical stage of Multiple Myeloma (MM) with the 5% of MGUS progresses to MM. Although the progression from MGUS to MM has not been completely characterized, it is possible to monitor the DNA modifications of patients diagnosed with MGUS to detect early specific genomic abnormalities, including copy number variations (CNV). The CNVs of chromosome 1q and chromosome 13q are associated with a worse prognosis in MM.

In the present study, we showed that it is possible to monitor the 1q21 gain and 13q deletion frequencies in gDNA using digital PCR. The CNV analysis of three cell lines with a well-characterized cytogenetic profile were compared with measures performed by a real-time PCR approach and with a digital PCR approach. Then, we analyzed CNVs in CD138⁺ plasma cells isolated from bone marrow of MGUS and MM patients.

Our results show that digital PCR and targeted DNA monitoring represent a specific and accurate technique for the early detection of specific genomic abnormalities both in MM and in MGUS patients.

Our results could represent a remarkable advancement in MM and MGUS diagnosis and in CNV analysis for the evaluation of the risk of progression from MGUS to MM.

KEYWORDS:

• MGUS
• MM
• CNVs detection
• digital PCR

Acknowledgments

The authors acknowledge the Multiple Myeloma Research Foundation for providing an updated and comprehensive real-life MM dataset for the international scientific community. The in silico analysis and the relative clinical correlation were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiative (https://research.themmrf.org/rp/terms).

Disclosure Statement

No potential conflicts of interest were disclosed.

Author contributions

F. S., C. C., and A.G. S. planned the research, coordinated the study, designed and performed most experiments, analyzed the respective data and drafted the manuscript. P. L. and P. P. participated in the design of the study and assisted in vitro experiments; A. V. and L. G. participated in the coordination of the study and assisted in manuscript preparation; A. G. and V. R. designed and supervised the research and drafted the manuscript; and all authors read and approved the final manuscript.

Additional information

Funding

This study was supported by the grants from Fondazione Puglia-Resources in the scientific and technological research field.Also supported by Regione Puglia (POR 2014-2020 Asse I – Azione 1.4.b. bando Innolabs “Telemielolab”) through a post doc fellowship (program no. 05.107 to CC), the Italian Association for Cancer Research (AIRC) through an Investigator Grants (no. 20441 to VR), and partially supported by the Apulian Regional Project “Medicina di Precisione” to AGS.