CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1− mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1− MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1−/D2− MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1−/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1− MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1− MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1− MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1−/D2−/D3− MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1− MCL.

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…Enhanced cyclin D1 effect in MCL is largely attributed to t(11;14) and the location of the CCND1 allele in the cytoplasm, nucleolin transcription factor‐rich areas in the perinucleolar area, and truncated mRNA of cyclin D1, which is associated with poor prognosis. In a subset of patients who are cyclin D1 negative, cyclin D2/cyclin D3 translocations are observed and are associated with SOX‐11 positivity and a similar genomic profile and clinical course to that of cyclin D1‐positive MCL. SOX‐11 overexpression —Overexpression of SOX‐11 is observed in a majority of MCL patients . This aberrancy impacts MCL cells in various ways—augmentation of BCR signaling, suppression of Bcl‐6 to avoid germinal center transit of MCL cells which remain having unmutated IGHV, activation of PAX‐5, blocking the maturation of B cells to plasma cells, promotion of angiogenesis via platelet derived growth factor alpha, and migration and adhesion of MCL cells to stromal cells via upregulation of CXCR4 and FAK (focal adhesion kinases) — leading to enhanced PI3K/AKT signaling and promoting cell‐adhesion‐mediated drug resistance. TP53 mutations —Mutations in TP53 lead to cell cycle upregulation, inhibition of apoptosis, and promotion of cell growth.…”

Cryptic insertions of the immunoglobulin light chain enhancer region near CCND1 in t(11;14)-negative mantle cell lymphoma

“…Copy number alterations were investigated using Oncoscan FFPE or SNP6.0 Array (ThermoFisher Scientific, Waltham, MA) and analyzed as described previously using Nexus Biodiscovery v9 (Biodiscovery, Hawthorne, CA, USA). 4,5 Paired-end whole-genome sequencing was performed on tumor and germline DNA from case 1 using standard Illumina protocols and sequenced in an Illumina HiSeq 2000 instrument. 4 Smufin, 6 Lumpy, 7 and custom algorithms were used to detect genome-wide structural variants (SV) and potential cryptic CCND1 rearrangements.…”

“…4,5 Paired-end whole-genome sequencing was performed on tumor and germline DNA from case 1 using standard Illumina protocols and sequenced in an Illumina HiSeq 2000 instrument. 4 Smufin, 6 Lumpy, 7 and custom algorithms were used to detect genome-wide structural variants (SV) and potential cryptic CCND1 rearrangements. Single nucleotide variant and indel calling was performed by Smufin and Sidrón, 8 and copy number alterations analysis was performed by Battenberg (https://github.com/cancerit/cgpBattenberg) (manuscript with additional details in preparation).…”

Application of Genomics to Clinical Practice in Haematological Malignancy

“…Although with the exception of FISH testing, most of the data analysis described for DLBCL, and FL remains in the research/clinical trial sphere, genetic testing is increasingly being applied to routine lymphoma diagnostics/management: Mantle cell lymphoma (MCL), an intermediate grade malignancy, is associated with t (11;14) IGH-CCND1 in~95% of cases (with the remainder likely associated with translocations of CCND2 or CCND3) which forms part of the diagnostic algorithm [111,112]. Demonstration of a TP53 mutation in MCL suggests patient will have a poor response to intensive chemoimmunotherapy followed by consolidative autologous HSCT opening the way for alternative innovative treatment approaches [113].…”