Abstract
Abstract 398
Most t(11;14)(q13;q32) breakpoints in mantle cell lymphoma (MCL) are scattered across a large genomic region centromeric to the CCND1 gene on chromosome 11q13. However, few t(11;14) breakpoints outside the major translocation cluster (MTC) have been sequenced. We report our analysis of 56 IGH-CCND1 fusion sequences from 32 non-MTC cases of MCL. Our analysis reveals remarkable breakpoint diversity at both CCND1 and IGH loci. The CCND1 breakpoints are located from 2 kb to 331 kb from the CCND1 gene, including 12 breakpoints (38%) in the 220kb region centromeric to the MTC, which is itself located 110 kb centromeric to the CCND1 gene. Twenty-one cases had a JH coding end breakpoint on the der(14) chromosome and a DH coding end breakpoint on the der(11). Two cases had der(14) and der(11) breakpoints derived from the coding and signal ends of the same JH or DH gene segment; one case had a JH/DH breakpoint on the der(14) and a VH breakpoint on the der(11); and one case had a breakpoint in the JH region located >100 bases from the nearest RSS motif, suggesting a RAG-independent break at IGH. No der(11) breakpoint could be amplified in eight cases. In sixteen cases (50%), one or both CCND1 breakpoints were within 4 bases of a CpG dinucleotide, a feature characteristic of translocation breakpoints in many human B cell lymphomas. Three CpG-associated “microclusters” were identified, i.e. breakpoints in two different tumors located at or near the same CpG site. Breakpoints in the sixteen (50%) “non-CpG” cases showed a significant association with AID hotspot motifs at the CCND1 locus. In addition, the non-CpG breakpoints were more likely to: 1) be located telomeric to the MTC, 2) involve 3' JH and 5' DH gene segments, and 3) be associated with immunoglobulin lambda light chain restriction; features that suggest occurrence at a late stage of pre-B cell maturation. In contrast, the CpG-associated breakpoints were: 1) more likely to be centromeric to the MTC, 2) not biased in their JH or DH segment usage, and 3) associated with kappa light chain restriction; features suggesting occurrence in an earlier pre-B cell or pro-B cell. Our results implicate AID in chromosomal breakage at both CpG and non-CpG sites within the CCND1 locus and suggest that AID and RAG collude to generate the chromosomal breaks underlying the t(11;14). Our findings also suggest that IGH-CCND1 rearrangements can occur at different stages of pre-B cell maturation. This study provides novel insights into the mechanism and developmental timing of the t(11;14) in human MCL, features that are likely to be relevant to a broad range of human lymphomas.
Disclosures:
Greisman: Signature Genomics, LLC: Patents & Royalties. Yi:Signature Genomics, LLC: Patents & Royalties.
UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells