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

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.

Figure 1

MYC locus breakpoints in myeloma. The locations of breakpoints are indicated by vertical lines corresponding in color to whether the partner chromosome belongs to an Ig loci (IGH@, IGK@ or IGL@; red) or a non-Ig locus (black). The genes and orientation are indicated according to their genomic location on chromosome 8. Arcs indicate the positions of two breakpoints found in one sample.

Figure 2

MYC rearrangements result in superenhancer colocalization on the derivative chromosome. Superenhancer elements are colocated near to MYC from a t(1;8) (top) or a t(8;22) (middle and bottom) where the partner chromosome gene (FAM46C, XBP1 and IGL, respectively) has a known function in myeloma or B-cell biology.

Figure 3

Expression of MYC in samples with a breakpoint is higher than in those without a breakpoint. (a) Expression data from 33 samples with sequence capture-determined translocations for those samples with no breakpoint at 8q24 (normal) and for those with an identified breakpoint (split MYC). (b) Expression data from 169 samples with any translocation detected by capture or FISH. Whisker plots show the 10–90 percentiles.

Figure 4

Progression-free survival (a) and Overall-free survival (b) in patients with a MYC breakpoint is significantly decreased compared with those without a breakpoint. PFS P=0.032, OS P=0.035. Data adjusted for confounding variables in Tables 4a, 4b and 4c.