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Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Richard Rosenquist)
Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Richard Rosenquist Brandell)ORCID iD: 0000-0002-9144-8710
Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
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2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. 2666-2670Article in journal (Refereed) Published
Abstract [en]

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

Place, publisher, year, edition, pages
2016. Vol. 128, no 23, p. 2666-2670
National Category
Hematology Clinical Laboratory Medicine
Research subject
Molecular Genetics; Pathology
Identifiers
URN: urn:nbn:se:uu:diva-314939DOI: 10.1182/blood-201603-704528ISI: 000392652300015PubMedID: 27670424OAI: oai:DiVA.org:uu-314939DiVA, id: diva2:1072287
Funder
German Research Foundation (DFG), DA1787/1-1Swedish Cancer SocietySwedish Research Council
Note

L.M., D.N., and E.Y. contributed equally to this study as joint first authors.

R.R. and F.D. contributed equally as joint senior authors.

Available from: 2017-02-07 Created: 2017-02-07 Last updated: 2019-03-29Bibliographically approved
In thesis
1. Recurrent Genetic Mutations in Lymphoid Malignancies
Open this publication in new window or tab >>Recurrent Genetic Mutations in Lymphoid Malignancies
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In recent years, the genetic landscape of B-cell derived lymphoid malignancies, including chronic lymphocytic leukemia (CLL), has been rapidly unraveled, identifying recurrent genetic mutations with potential clinical impact. Interestingly, ~30% of all CLL patients can be assigned to more homogeneous subsets based on the expression of a similar or “stereotyped” B-cell receptor (BcR). Considering that biased distribution of genetic mutations was recently indicated in specific stereotyped subsets, in paper I, we screened 565 subset cases, preferentially assigned to clinically aggressive subsets, and confirm the SF3B1 mutational bias in subset #2 (45%), but also report on similarly marked enrichment in subset #3 (46%). In contrast, NOTCH1 mutations were predominantly detected in subsets #1, #8, #59 and #99 (22-34%). This data further highlights a subset-biased acquisition of genetic mutations in the pathogenesis of at least certain subsets. Aberrant NF-κB signaling due to a deletion within the NFKBIE gene previously reported in CLL warranted extended investigation in other lymphoid malignancies. Therefore, in paper II, we screened 1460 patients with various lymphoid malignancies for NFKBIE deletions and reported enrichment in classical Hodgkin lymphoma (27%) and primary mediastinal B-cell lymphoma (PMBL) (23%). NFKBIE-deleted PMBL cases had higher rates of chemorefractoriness and inferior overall survival (OS). NFKBIE-deletion status remained an independent prognostic marker in multivariate analysis. EGR2 mutations were recently reported in advanced stage CLL patients; thus, in paper III we screened 2403 CLL patients for mutations in EGR2. An overall mutational frequency of 3.8% was reported and EGR2 mutations were associated with younger age, advanced stage and del(11q). EGR2 mutational status remained an independent marker of poor outcome in multivariate analysis, both in the screening and validation cohorts. Whole-genome sequencing (WGS) of 70 CLL cases, assigned to poor-prognostic subsets #1 and #2 and indolent subset #4, were investigated in Paper IV and revealed a similar skewing of SF3B1 mutations in subset #2 and NOTCH1 mutations in subset #1 to that reported in Paper I. Additionally, an increased frequency of the recently proposed CLL driver gene RPS15 was observed in subset #1. Finally, novel non-coding mutational biases were detected in both subset #1 and #2 that warrant further investigation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 82
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1312
Keywords
Lymphoid malignancies, mutations, CLL, stereotypy, subsets, PMBL, NFKBIE, EGR2, whole-genome sequencing
National Category
Cancer and Oncology Hematology
Research subject
Molecular Genetics; Oncology
Identifiers
urn:nbn:se:uu:diva-314956 (URN)978-91-554-9850-4 (ISBN)
Public defence
2017-05-05, Rudbecksalen, Dag Hammarskjölds Väg 20, Uppsala, 13:15 (English)
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Supervisors
Available from: 2017-04-07 Created: 2017-03-13 Last updated: 2017-04-21

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Mansouri, LarryYoung, EmmaAbdulla, MaysaaLjungström, ViktorSkaftason, AronPandzic, TatjanaEnblad, GunillaRosenquist, Richard

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