Programmpunkt

14:45–15:00

Titel: Genetic and epigenetic characterization of chronic lymphocytic leukemia with translocations involving the immunoglobulin loci
ID: W8-004
Art: Invited talk
Redezeit: 15 min
Session: Workshop 8
(Epi-)Genomics and Cancer

Referent: Cosima Drewes (Ulm/DE)


Abstract - Text

Abstract-Text

Immunoglobulin (IG) translocations occur frequently in various B-cell neoplasms and at least in part of the malignancies, constitute diagnostic or prognostic markers. They act predominantly via IG-enhancer hijacking, and thus, lead to the overexpression of oncogenes on the translocation partners. Approximately 5-10 % of cases of B-cell chronic lymphocytic leukemia (CLL) harbor IG translocations. Known IG translocation partners in CLL include BCL2, BCL3, BCL10, BCL11A and MYC. However, a large part of partner genes and functional significance are still unknown and many of these subgroups are insufficiently characterised to date. Therefore, the present project aims at characterizing IG translocated CLLs on the genomic, epigenomic and transcriptional level and to translate the molecular findings into clinically applicable biomarkers.


Using Fluorescence in situ hybridization (FISH), we have so far identified a total of 275 cases of (or resembling) CLL with breakpoints in one of the IG loci, excluding cases with t(11;14) and t(14;18).  Using break-apart and double color double fusion probes by FISH the most common partners identified are BCL3 in 29 % and MYC in 15 % of cases.  In the majority of cases the partner remained unresolved by FISH. These samples with an unknown break are currently analysed by targeted capture-based sequencing to identify novel translocation partners.


We generated global DNA methylation profiles using 850K EPIC and 450K BeadChip arrays of 139 samples focusing on cases with identified and recurrent translocation partner genes. Copy number variant (CNV) analysis of these samples revealed an, as compared to CLL in general, biased distribution of additional alterations, with higher frequency of trisomy 12 (37 %) and lower frequency of deletion 13q (16 %). Deletion of 11q was present in 22 % and deletion in 17p in 13 % of cases. Deletions in the IGH, IGK and IGL loci indicating clonal rearrangements of these loci were detected in 85 %, 49 % and 32 % of cases, respectively. Regarding IGHV somatic hypermutation 26 % of cases had a mutated IGHV status and 55 % an unmutated IGHV (19 % unknown). Analyses for IGHV subset assignment as well as, frequent gene mutations such as TP53, NOTCH1, SF3B1 are ongoing.


Our analyses on a large cohort of CLLs with IG translocation gives an overview of the distribution of translocation partners and provide novel insights into the genetic and epigenetic landscapes of IG translocated CLL.