Transcriptional dysregulation of the deleted in colorectal carcinoma gene in multiple myeloma and monoclonal gammopathy of undetermined significance

Abstract

The deleted in colorectal carcinoma (DCC) gene at 18q21 encodes a netrin‐1 receptor, a tumor suppressor that prevents cell growth. While allele loss or decreased expression of DCC has been associated with the progression of solid tumors and hematologic malignancies, including leukemias and malignant lymphomas, its involvement has not been evaluated in multiple myeloma (MM), a plasma cell malignancy characterized by complex and heterogenous molecular abnormalities. We here show that 10 of 11 human myeloma‐derived cell lines (HMCLs) expressed non‐translated aberrant DCC transcriptional variants, in which exon 2 fuses with intron 1 instead of exon 1 (mt.DCC). Among them, two co‐expressed wild type transcripts (wt.DCC), while eight co‐expressed the splicing variant (sv.DCC) lacking exon 1. The remaining HMCL expressed only sv.DCC. In addition, analyses revealed that there were two types of mt.DCC that differed in their fusion of intron 1 with exon 2. In patient‐derived samples from 30 MM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients, wt.DCC was expressed in 53% of MM, but not in MGUS, while 23% of MM and 75% of MGUS expressed only sv.DCC. Considering that 25% of MGUS, 57% of MM, and 91% HMCLs expressed mt.DCC, our results suggest that the acquisition of mt.DCC might be a secondary genetic change in plasma cell dyscrasia. © 2015 Wiley Periodicals, Inc.

Therapeutic Targets and Signaling Pathways for Diagnosis of Myeloma

“…DNA-based studies in MM, including mainly whole exome sequencing, have emphasized the mutational background of the disease, which includes few repeated mutations (NRAS, KRAS, TP53, DIS3, and FAM46C). NFkB and ERK trails are the most involved pathways, with mutations in 43 and 17% of MM cases respectively [111][112][113][114].…”

“…Some mutations can also be assessed to predict drug sensitivity. Initial data of one study, revealed that the presence of NRAS mutations in relapsed cases is associated with inferior response to bortezomib [138] or in contrast, that the occurrence of IRF4 mutations is related with higher sensitivity to immuno-modulatory agents [111]. These data needs confirmation in further clinical trials but it is hypothesis generating study.…”

Utilizing next-generation sequencing in the management of multiple myeloma

“…This could be particularly meaningful in MM, where disease-specific alternate splicing events of several genes have been reported [76,77,78]. Moreover, RNA-seq is the technology of choice for the discovery and genome-wide expression analysis of non-coding RNAs, whose involvement in MM is increasingly documented and that are being investigated as a therapeutic target [79,80].…”

Gene Expression Profiles in Myeloma: Ready for the Real World?

“…It has been recognized as important mediators of malignant phenotype and the understanding of the alternate splicing events will contribute in the next future to better establish prognosis in MM. Some reports have shown that splicing events affecting specific genes as hyaluronan synthase 1 ( HAS1 ) (34,35) or deleted in colorectal carcinoma gene ( DCC ) occur recurrently in MM (36), or that a strategy targeting the splicing of X-box binding protein 1 ( XBP1 ) increases sensitivity of MM cells to proteasome inhibitor. Pilot investigations by our group as well as others have identified significant number of spliced isoforms in myeloma in comparison to normal plasma cells with both functional consequence as well as prognostic implications.…”