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Recurrent Genetic Mutations in Lymphoid Malignancies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. (Richard Rosenquist Brandell)ORCID iD: 0000-0002-9144-8710
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 [en]
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: urn:nbn:se:uu:diva-314956ISBN: 978-91-554-9850-4 (print)OAI: oai:DiVA.org:uu-314956DiVA, id: diva2:1081342
Public defence
2017-05-05, Rudbecksalen, Dag Hammarskjölds Väg 20, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-04-07 Created: 2017-03-13 Last updated: 2017-04-21
List of papers
1. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
Open this publication in new window or tab >>Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 8, p. 959-967Article in journal (Refereed) Published
Abstract [en]

We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets# 2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-304419 (URN)10.3324/haematol.2016.141812 (DOI)000381941900019 ()27198719 (PubMedID)
Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2017-11-30Bibliographically approved
2. Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
Open this publication in new window or tab >>Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
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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.

National Category
Hematology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-314939 (URN)10.1182/blood-201603-704528 (DOI)000392652300015 ()27670424 (PubMedID)
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: 2017-11-29Bibliographically approved
3. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
Open this publication in new window or tab >>EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1547-1554Article in journal (Refereed) Published
Abstract [en]

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-314928 (URN)10.1038/leu.2016.359 (DOI)000404745300009 ()27890934 (PubMedID)
Note

E.Y. and D.N. 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: 2017-09-28Bibliographically approved
4. Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
Open this publication in new window or tab >>Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-302024 (URN)
External cooperation:
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2016-08-28 Created: 2016-08-28 Last updated: 2018-01-10

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