Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients

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Abstract

Secondary MYC translocations in myeloma have been shown to be important in the pathogenesis and progression of disease. Here, we have used a DNA capture and massively parallel sequencing approach to identify the partner chromosomes in 104 presentation myeloma samples. 8q24 breakpoints were identified in 21 (20%) samples with partner loci including IGH, IGK and IGL, which juxtapose the immunoglobulin (Ig) enhancers next to MYC in 8/23 samples. The remaining samples had partner loci including XBP1, FAM46C, CCND1 and KRAS, which are important in B-cell maturation or myeloma pathogenesis. Analysis of the region surrounding the breakpoints indicated the presence of superenhancers on the partner chromosomes and gene expression analysis showed increased expression of MYC in these samples. Patients with MYC translocations had a decreased progression-free and overall survival. We postulate that translocation breakpoints near MYC result in colocalization of the gene with superenhancers from loci, which are important in the development of the cell type in which they occur. In the case of myeloma these are the Ig loci and those important for plasma cell development and myeloma pathogenesis, resulting in increased expression of MYC and an aggressive disease phenotype.

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Most cited references 22

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A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value.

Scott Boyd, Matthew W. Jenner, Gareth J. Morgan … (2010)

To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25%), 12p (15%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%), and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescence in situ hybridization and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes that have functions relevant to myeloma biology. Taken together, these analyses indicate that the crucial pathways in myeloma pathogenesis include the nuclear factor-κB pathway, apoptosis, cell-cycle regulation, Wnt signaling, and histone modifications. This study was registered at http://isrctn.org as ISRCTN68454111.

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Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival.

Hanne B. Walker, Laura Chiecchio, … (2011)

Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact. Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data. 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting. Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations. ©2011 AACR.

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Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors.

Florence Magrangeas, F Gerson, Hervé Avet-Loiseau … (2001)

Rearrangements of the c-myc oncogene have been found in most plasmacytomas induced in mice and human myeloma cell lines (HMCLs) analyzed so far. However, neither induced mouse plasmacytomas nor HMCLs represent relevant models for human multiple myeloma (MM). To evaluate the incidence of c-myc rearrangements in human plasma cell dyscrasias, sets of probes were generated to allow direct assessment of c-myc translocations on interphase plasma cells by using fluorescence in situ hybridization. After validation of these probes, a large cohort of patients with either newly diagnosed MM (n = 529), relapsed MM (n = 58), primary plasma cell leukemia (PCL; n = 23), monoclonal gammopathy of undetermined significance (n = 65), or smoldering MM (n = 24) were analyzed. C-myc rearrangements were identified in 15% of patients with MM or primary PCL, independently of the stage of the disease (ie, diagnosis or relapse and MM or primary PCL). Analysis of the 2 main translocations observed on karyotyping, ie, t(8;14) and t(8;22), revealed that these specific translocations represented only 25% (23 of 91) of c-myc rearrangements. c-myc rearrangements were then correlated with several other patients' characteristics: illegitimate IgH recombinations, chromosome 13 deletions, and serum beta2-microglobulin levels. The only significant correlation was with a high beta2-microglobulin level (P =.002), although a trend for association with t(4;14) was observed (P =.08). Thus, c-myc rearrangement analysis in patients with MM revealed a strikingly lower incidence than that in HMCLs and plasmacytomas induced in mice, indicating that data obtained with these models cannot be directly extrapolated to human MM.

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Author and article information

Journal

Journal ID (nlm-ta): Blood Cancer J

Journal ID (iso-abbrev): Blood Cancer J

Title: Blood Cancer Journal

Publisher: Nature Publishing Group

ISSN (Electronic): 2044-5385

Publication date (Print): March 2014

Publication date (Electronic): 14 March 2014

Publication date PMC-release: 1 March 2014

Volume: 4

Issue: 3

Page: e191

Affiliations

[1 ]Division of Molecular Pathology, The Institute of Cancer Research , London, UK

[2 ]Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi , Bologna, Italy

[3 ]Wessex Regional Genetics Laboratory, Salisbury District Hospital , Salisbury, UK

[4 ]Divisions of Molecular Pathology, Cancer Therapeutics and Clinical Sciences, The Institute of Cancer Research , London, UK

Author notes

[* ]Division of Molecular Pathology, The Institute of Cancer Research , London SM2 5NG, Surrey, UK. E-mail: gareth.morgan@ 123456icr.ac.uk

Article

Publisher Item ID: bcj201413

DOI: 10.1038/bcj.2014.13

PMC ID: 3972699

PubMed ID: 24632883

SO-VID: 5eee76a0-0e16-496c-9b3e-8ed3f8e7829e

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients

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Most cited references 22

A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value.

Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival.

Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors.

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