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. 2018 Oct 23;2(20):2755-2765.
doi: 10.1182/bloodadvances.2018023572.

High-resolution Architecture and Partner Genes of MYC Rearrangements in Lymphoma With DLBCL Morphology

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Free PMC article

High-resolution Architecture and Partner Genes of MYC Rearrangements in Lymphoma With DLBCL Morphology

Lauren C Chong et al. Blood Adv. .
Free PMC article

Abstract

Genomic rearrangements in the MYC locus occur in ∼12% of lymphomas with diffuse large B-cell lymphoma (DLBCL) morphology and are associated with inferior outcome. Previous studies exploring MYC rearrangements have primarily used fluorescence in situ hybridization (FISH) assays to characterize break-apart status but have rarely examined breakpoint location, and in some cases have not examined partner identity. We performed targeted sequencing of MYC, BCL2, BCL6, and the immunoglobulin (IG) loci in 112 tumors with DLBCL morphology harboring MYC rearrangement. We characterized the location of the MYC rearrangement at base pair resolution and identified the partner in 88 cases. We observed a cluster of breakpoints upstream of the MYC coding region and in intron 1 (the "genic cluster"). Genic cluster rearrangements were enriched for translocations involving IGH (80%), whereas nongenic rearrangements occurred mostly downstream of the MYC gene with a variety of partners, including IGL and IGK Other recurrent partners included BCL6, ZCCHC7, and RFTN1, which has not previously been described as a MYC partner. We compared 2 commercially available FISH break-apart assays for the MYC locus and observed discordant results in 32% of cases examined, including some with MYC-IGL and MYC-IGK rearrangements. In cases of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH), so-called "double-hit" lymphomas, the majority of MYC rearrangements had non-IG partners (65%), with breakpoints outside the genic cluster (72%). In patients with de novo HGBL-DH of DLBCL morphology, MYC-IG rearrangements showed a trend toward inferior time to progression and overall survival compared with MYC-non-IG rearrangements. Our data reveal clinically relevant architecture of MYC rearrangements in lymphomas with DLBCL morphology.

Conflict of interest statement

Conflict-of-interest disclosure: C.F. receives research funding from Roche/Genentech and honoraria from AbbVie, Seattle Genetics, and Roche/Genentech. The remaining authors declare no competing financial interests.

Figures

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Figure 1.
Figure 1.
Cohort selected for capture sequencing. (A) Biopsies from de novo DLBCL or tFL with DLBCL morphology were selected for inclusion if they were break-apart positive (BA+) at the MYC locus using the Vysis and/or Dako FISH assays. Cases with no available FFPE tissue were excluded, leaving a total of 112 cases. (B) The FISH break-apart (BA) status of the 112 cases are summarized. Cases in red boxes represent those successfully assessed with the Dako assay. ND, not done.
Figure 2.
Figure 2.
SVs in the MYC locus discovered by targeted capture sequencing. The horizontal axis represents genomic space on chromosome 8 (chr8). The upper panel summarizes the whole MYC capture region, and the bottom panel zooms in to the gene region. In each panel, the top track shows the location of translocation breakpoints (vertical ticks on the axis), and partner information is summarized with symbols above. The middle track shows gene models in the region. The bottom track shows the location of intrachromosomal rearrangements, with rectangles representing the span of the rearrangements. Arrows indicate that the end of the rearrangement is located outside of the plotting region at the labeled location. In the upper panel, rearrangements in the genic cluster have been binned for visualization. Additional middle tracks in the upper panel show the approximate location of reported enhancer regions (blue boxes) and the approximate binding location of FISH break-apart probes (green Vysis probe binds downstream of the plotted region). The shaded gray rectangle shows the captured region. Rearrangements that failed validation and low-confidence predictions in nonvalidated cases have been omitted. Intrachromosomal rearrangements smaller than 2 Mb have not been plotted, and rearrangements for which both reciprocal events were identified have only 1 displayed.
Figure 3.
Figure 3.
Identity and location of MYC rearrangement partners throughout the genome. (A) Circos plot showing identified rearrangement partners of MYC. Black arches represent translocations with thickness representing recurrence. Chromosomes with no identified partners are not drawn. Regions included in the capture space are labeled in green. (B) Absolute frequency of recurrent MYC rearrangement partners.
Figure 4.
Figure 4.
Sensitivity of rearrangement detection at the MYC locus with Vysis and Dako FISH probes. The horizontal axis represents genomic space on chromosome 8 (chr8). Translocations are represented by vertical ticks along the axis, with symbols describing the rearrangement partner labeled above. White crosses denote cases that were MYC break-apart positive by Dako only (ie, Vysis failed). The shaded blue region represents the space where rearrangements can be detected by both assays, and the shaded purple region shows where only Vysis can detect rearrangements. The approximate location of FISH binding probes is shown on the middle track. Representative FISH images show observed patterns: cases in the blue region produce a fusion signal and a break-apart signal in both assays (left); cases with breakpoints that lie within the Dako red probe binding region produce 2 fusion signals and a small additional red signal, as indicated by the white arrow (center); and cases in the purple region produce a break-apart signal with Vysis and 2 fusion signals with Dako (right). Breakpoints corresponding to the FISH images are indicated by black arrows under the chromosome track.
Figure 5.
Figure 5.
Translocation breakpoints in the IGH locus. The horizontal axis represents genomic space on chromosome 14 (chr14). The top panel shows the full IGH locus, the middle panel shows an enlargement of the constant region, and the bottom panel shows the smaller region surrounding the end of the variable diversity joining genes. In each panel, the top track indicates the location of translocation breakpoints (vertical tick marks), with symbols describing the identity of the partner region labeled above. Breakpoints shown on the uppermost panel have been binned for visualization. Annotations of the variable diversity joining segments, constant regions, and enhancer elements (Eµ and 3′RR) are depicted below.

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