The Prognostic Role of MYC Structural Variants Identified by NGS and FISH in Multiple Myeloma

Abstract

Purpose: Structural variants (SV) of the MYC gene region are common in multiple myeloma (MM) and influence disease progression. However, the prognostic significance of different MYC SVs in MM has not been clearly established. Experimental design: We conducted a retrospective study of MM comparing MYC SV subtypes identified by next generation sequencing (NGS) and fluorescence in situ hybridization (FISH) to MYC expression and disease survival using 140 cases from Mayo Clinic and 658 cases from the MMRF CoMMpass study. Results: MYC SVs were found in 41% of cases and were classified into 9 subtypes. A correlation between the presence of a MYC SV and increased MYC expression was identified. Among the 9 MYC subtypes, the non-Ig insertion subtype was independently associated with improved outcomes, while the Ig insertion subtype, specifically involving the IgL gene partner, was independently associated with poorer outcomes compared to other MYC SV subtypes. Although the FISH methodology failed to detect ~70% of all MYC SVs, those detected by FISH were associated with elevated MYC gene expression and poor outcomes suggesting a different pathogenic role for FISH-detected MYC subtypes compared to other MYC subtypes. Conclusion: Understanding the impact of different MYC SVs on disease outcome is necessary for the reliable interpretation of MYC SVs in MM. NGS approaches should be considered as a replacement technique for a more comprehensive evaluation of the MM clone.