CRYPTIC INSERTIONS OF IMMUNOGLOBULIN LIGHT CHAIN ENHANCER REGIONS ACTIVATE CCND3 AND CCND2 IN CYCLIN D1-NEGATIVE MANTLE CELL LYMPHOMAS
Author(s): ,
David Martín-Garcia
Affiliations:
IDIBAPS,Barcelona,Spain
,
Alba Navarro
Affiliations:
IDIBAPS,Barcelona,Spain
,
Guillem Clot
Affiliations:
IDIBAPS,Barcelona,Spain
,
Inmaculada Ribera-Cortada
Affiliations:
IDIBAPS,Barcelona,Spain
,
Blanca González-Farré
Affiliations:
IDIBAPS,Barcelona,Spain
,
Jesús Gutiérrez-Abril
Affiliations:
Universidad de Oviedo,Oviedo,Spain
,
Rafael Valdés-Mas
Affiliations:
Universidad de Oviedo,Oviedo,Spain
,
Renata Woroniecka
Affiliations:
The Maria Skłodowska-Curie Institute - Oncology Center,Warsaw,Poland
,
Grzegorz Rymkiewicz
Affiliations:
The Maria Skłodowska-Curie Institute - Oncology Center,Warsaw,Poland
,
Laurence de Leval
Affiliations:
Centre Hospitalier Universitaire Vaudois,Lausanne,Switzerland
,
Andreas Rosenwald
Affiliations:
University of Würzburg,Würzburg,Germany
,
Judith A. Ferry
Affiliations:
Massachusetts General Hospital and Harvard Medical School,Massachusetts,United States
,
Eric D Hsi
Affiliations:
Cleveland Clinic Foundation,Cleveland,United States
,
Kai Fu
Affiliations:
University of Nebraska Medical Center,Omaha, NE,United States
,
Jan Delabie
Affiliations:
University of Toronto and Oslo University Hospital,Oslo,Norway
,
Dennis Weisenburger
Affiliations:
Department of Pathology, City of Hope National Medical Center,Duarte, CA,United States
,
Daphne de Jong
Affiliations:
VU University Medical Center,Amsterdam,Netherlands
,
Sheila J O'Connor
Affiliations:
HMDS Laboratory, Leeds Teaching Hospitals NHS Trust, St James’s Institute of Oncology,Leeds,United Kingdom
,
Steven H Swerdlow
Affiliations:
Department of Pathology, University of Pittsburgh School of Medicine,Pittsburgh, PA,United States
,
David Torrents
Affiliations:
Barcelona Supercomputing Center,Barcelona,Spain
,
Sergi Beltran
Affiliations:
Centro Nacional de Análisis Genómico-Centre for Genomic Regulation,Barcelona,Spain
,
Blanca Espinet
Affiliations:
IMIM-Hospital del Mar,Barcelona,Spain
,
Estella Matutes
Affiliations:
Hospital Clinic de Barcelona,Barcelona,Spain
,
Reiner Siebert
Affiliations:
Institute of Human Genetics, University of Ulm,Ulm,Germany
,
German Ott
Affiliations:
Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology,Stuttgart,Germany
,
Leticia Quintanilla-Martinez
Affiliations:
Institute of Pathology, Eberhard-Karls-University of Tübingen,Tübingen,Germany
,
Elaine S Jaffe
Affiliations:
National Cancer Institute, National Institutes of Health,Bethesda,United States
,
Carlos López-Otín
Affiliations:
Universidad de Oviedo,Oviedo,Spain
,
Xose S. Puente
Affiliations:
Universidad de Oviedo,Oviedo,Spain
,
Elias Campo
Affiliations:
IDIBAPS,Barcelona,Spain
,
Itziar Salaverria
Affiliations:
IDIBAPS,Barcelona,Spain
Sílvia Beà
Affiliations:
IDIBAPS,Barcelona,Spain
(Abstract release date: Jun 8, 2017) EHA Learning Center. Bea S. Jun 25, 2017; 183929
Silvia Bea
Silvia Bea
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Abstract: LB2601

Type: Late Breaking Oral Session

Presentation during EHA22: On Sunday, June 25, 2017 from 12:00 - 12:15

Location: Hall A

Background

Mantle cell lymphomas (MCL) are characterized by the primary translocation t(11;14)(q13;q32) involving CCND1 and IGH genes in virtually all cases. Recently, a small subset of cyclin D1-negative (cyclin D1) MCL has been recognized. About half of these cases have CCND2 gene rearrangements and overexpression of this gene. However, the primary oncogenic events in cyclin D1/cyclin D2MCL still remain elusive. 

Aims
To identify potential mechanisms driving the pathogenesis of cyclin D1/cyclin D2MCL. 

Methods
We investigated 66 cyclin D1/SOX11+ MCL cases by a combination of fluorescence in situ hybridization (FISH), gene expression profiling by Affymetrix U133+2.0 and qPCR (n=51), and copy number arrays (n=47) (Agilent CGH 1M, Affymetrix Oncoscan and 500K). Six cases were investigated by genome-wide sequencing including 4 mate-pair whole-genomes, 4 whole exomes, and 1 whole-genome sequencing. The male/female ratio was 2.5:1 and median age at diagnosis 66 years.

Results
Most cyclin D1MCL (49/51, 96%) showed overexpression of other G1 cyclins: CCND2 in 33/50 (66%), CCND3 in 12/51 (24%), and moderate overexpression of both CCNE1 and CCNE2 in 4/35 (11%). CCND2 rearrangements were detected by FISH in 25/33 cases (76%) with CCND2 overexpression, but the remaining CCND2+ cases and those with CCND3 overexpression did not show CCND2, CCND3 and IG rearrangements using currently used break-apart probes. Interestingly, by mate-pair whole-genome and whole-exome sequencing analyses we discovered cryptic insertions of IG light chain regions including the enhancer regulatory elements (2 IGK and 1 IGL) near CCND3 gene in the three cases with cyclin D3 overexpression. These rearrangements were confirmed by Sanger sequencing and FISH with specifically designed probes to recognize the cryptically rearranged regions. Furthermore, using these probes we detected 6 additional cases with cryptic IGK-CCND3, as well as 3 cases with IGK-CCND2 juxtaposition in tumors with high levels of CCND3 and CCND2, respectively.  Taken together, 74% and 18% cases corresponded to cyclin D2+ and cyclin D3+ MCL, respectively, whereas 6% showed overexpression of CCNE1 and CCNE2 without gene rearrangements. The whole-genome analysis of one cyclin D1 MCL with CCNE1 and CCNE2 overexpression identified 29 somatic protein-coding mutations, 42 complex structural variants and 24 copy number alterations (including CDKN2A and RB1 homozygous deletions) but not rearrangements  involving any of the IG genes or G1 cyclins. The global genomic profile of 47 cyclin D1 MCL was highly complex (mean 13 alterations/case) and similar to 102 conventional SOX11+ MCL, with significantly more gains at 7p and 18q in the cyclin D1 MCL. Moreover, 32% cases had chromothripsis at least in one chromosome.

Conclusion
We have identified a novel IG light chain locus-associated rearrangement, consisting of cryptic insertion of IG enhancer near CCND3 gene that leads to cyclin D3 overexpression. Similarly, we found cryptic insertions of IGK enhancer region into CCND2 gene. Both aberrations were undetectable by cytogenetics and FISH break-apart approaches. Overall, 65/66 (98%) MCL had G1 cyclin overexpression. The detection of these rearrangements with custom FISH probes or that of high levels of CCND2 or CCND3 by qPCR, together with SOX11 expression, are helpful diagnostic tools to recognize cyclin D1 MCL and provide insights on the pathogenesis of this rare subgroup.

Session topic: 18. Non-Hodgkin & Hodgkin lymphoma - Biology

Keyword(s): Cyclin D1, Diagnosis, Mantle cell lymphoma, Translocation

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