title: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Nagoshi
authors.affiliation: Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Chinen
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Tatekawa
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Maegawa
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Yamamoto-Sugitani
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.|Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tsutsumi
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horiike
authors.affiliation: Department of Hematology, Kumamoto University School of Medicine, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Hematology, Kumamoto University School of Medicine, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Fujiwara
authors.affiliation: Division of Informative Clinical Science, Kumamoto University, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hata
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan.|Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D000075389:DCC Receptor; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005091:Exons; D016147:Genes, Tumor Suppressor; D006801:Humans; D007438:Introns; D019656:Loss of Heterozygosity; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009101:Multiple Myeloma / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D053668:Syndecan-1 / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C000595707:BCL2 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; D000075389:DCC Receptor; C501909:DCC protein, human; D004268:DNA-Binding Proteins; C489325:MBD2 protein, human; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D053668:Syndecan-1; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein