Immunohistochemistry for identification of CCND1, NSD2, and MAF gene rearrangements in plasma cell myeloma

Abstract

The t(11;14)/CCND1‐IGH, t(4;14)/NSD2(MMSET)‐IGH, and t(14;16)/IGH‐MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost‐ and time‐efficient, and can be readily applied to routinely prepared formalin‐fixed, paraffin‐embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1, NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut‐off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut‐off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC.

hsa_circ_0007841: A Novel Potential Biomarker and Drug Resistance for Multiple Myeloma

“…It has been shown that some genetic mutations are closely related to the poor outcome of MM, including chromosomal alterations t (4; 14), t (14; 16), and t (14; 20). Due to chromosomal translocation, oncogenes such as MMSET/FGFR3, CCND3, CCND1, MAF, and MAFB are still regulated by the IgH gene enhancer and their expressions increase (11, 32). As a result, the cyclin D family members are upregulated, leading to the dysregulation of the G1/S checkpoint.…”

Molecular basis of clonal evolution in multiple myeloma

“…The t(4;14)(p16;q32) translocation results in deregulation of the histone methyltransferase MMSET (also known as WHSC1/ NSD2/KMT3G) [29,30], which causes an increase in the H3K36me2 level and a decrease in the H3K27me3 level in the entire genome, resulting in derangement of transcriptional programs including cyclin D2 overexpression [31,32]. The translocations t(14;16)(q32;q23) and t(14;20)(q32;q11) up-regulate Maf family transcription factors c-Maf and MafB, the target genes of which also include cyclin D2 [33]. On the other hand, the precise mechanism by which hyperdiploidy transforms plasma cells is not yet understood; however, the most prevalent (~ 30%) hyperdiploid aberration, trisomy 11, may cause cyclin D1 overexpression due to an increase in gene dosage.…”