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Genetic and Epigenetic Profiling of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Rosenquist Brandell)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) both belong to the group of mature B-cell malignancies. However, MCL is typically clinically aggressive while the clinical course of CLL varies. CLL can be divided into prognostic subgroups based on IGHV mutational status and into multiple subsets based on closely homologous (stereotyped) B-cell receptors. In paper I we investigated 31 MCL cases using high-density 250K single-nucleotide polymorphism arrays and gene expression arrays. Although most copy-number aberrations (CNAs) were previously reported in MCL, a novel deletion was identified at 20q (16%) containing the candidate tumor suppressor gene ZFP64. A high proliferation gene expression signature was associated with poor prognosis, large CNAs, 7p gains and 9q losses. Losses at 1p/8p/13q/17p were associated with increased genomic complexity. In paper II we sequenced exons 4 to 8 of the TP53 gene in 119 MCL cases. 17p copy-number status was known from previous studies or determined by real-time quantitative polymerase chain reaction. TP53 mutations were detected in 14% of cases and were strongly associated with poor survival while 17p deletions were more common (32%) but did not predict survival. In papers III and IV we applied high-resolution genomic 27K methylation arrays to 20 MCL and 39 CLL samples. In paper III MCL displayed a homogenous methylation profile without correlation with the proliferation signature whereas MCL was clearly separated from CLL. Gene ontology analysis revealed enrichment of developmental genes, in particular homeobox transcription factor genes, among targets methylated in MCL. In paper IV we compared three different stereotyped CLL subsets: #1 (IGHV unmutated), #2 (IGHV3-21) and #4 (IGHV mutated). Many genes were differentially methylated between each two subsets and immune response genes (e.g. CD80 and CD86) were enriched among genes methylated in subset #1 but not in subsets #2/#4.

In summary, CNAs were frequent and not random in MCL. Specific CNAs correlated with a high proliferation gene expression signature or genomic complexity. TP53 mutations predicted short survival whereas 17p deletions did not. A high proliferation signature was not associated with differential DNA methylation in MCL, which demonstrated a homogeneous methylation pattern. In contrast, genomic methylation patterns differed between MCL and CLL and between stereotyped CLL subsets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 699
Keyword [en]
mantle cell lymphoma, chronic lymphocytic leukemia, copy number aberration, proliferation signature, TP53, SNP array, methylation array
National Category
Hematology Medical Genetics Biochemistry and Molecular Biology Cell and Molecular Biology
Research subject
Medical Genetics; Oncology; Molecular Medicine; Pathology
Identifiers
URN: urn:nbn:se:uu:diva-156786ISBN: 978-91-554-8146-9 (print)OAI: oai:DiVA.org:uu-156786DiVA: diva2:438828
Public defence
2011-10-21, Gustavianum, Akademigatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2011-09-30 Created: 2011-08-09 Last updated: 2011-11-03Bibliographically approved
List of papers
1. High-resolution genomic screening in mantle cell lymphoma: specific changes correlate with genomic complexity, the proliferation signature and survival
Open this publication in new window or tab >>High-resolution genomic screening in mantle cell lymphoma: specific changes correlate with genomic complexity, the proliferation signature and survival
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2011 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 50, no 2, 113-121 p.Article in journal (Refereed) Published
Abstract [en]

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) and numerous copy number aberrations (CNAs). Recently, gene expression profiling defined a proliferation gene expression signature in MCL where high scores predict shorter survival. We investigated 31 MCL cases using high-density single nucleotide polymorphism arrays and correlated CNA patterns with the proliferation signature and with clinical data. Many recurrent CNAs typical of MCL were detected, including losses at 1p (55%), 8p (29%), 9q (29%), 11q (55%), 13q (42%) and 17p (32%), and gains at 3q (39%), 8q (26%), 15q (23%) and 18q (23%). A novel deleted region at 20q (16%) contained only one candidate gene, ZFP64, a putative tumor suppressor. Unsupervised clustering identified subgroups with different patterns of CNAs, including a subset (19%) characterized by the presence of 11q loss in all cases and by the absence of 13q loss, and 3q and 7p gains. Losses at 1p, 8p, 13q and 17p were associated with increased genomic complexity. High proliferation signature scores correlated with increased number of large (>15 Mbp) CNAs (P = 0.03) as well as copy number gains at 7p (P = 0.02) and losses at 9q (P = 0.04). Furthermore, large/complex 13q losses were associated with improved survival (P < 0.05) as were losses/copy number neutral LOH at 19p13 (P = 0.01). In summary, this high-resolution genomic analysis identified novel aberrations and revealed that several CNAs correlated with genomic complexity, the proliferation status and survival.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-141644 (URN)10.1002/gcc.20836 (DOI)000285263800005 ()21117067 (PubMedID)
Available from: 2011-01-12 Created: 2011-01-12 Last updated: 2017-12-11Bibliographically approved
2. Impact of TP53 mutation and 17p deletion in mantle cell lymphoma
Open this publication in new window or tab >>Impact of TP53 mutation and 17p deletion in mantle cell lymphoma
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2011 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551Article in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156780 (URN)10.1038/leu.2011.162 (DOI)000298405500015 ()21720382 (PubMedID)
Available from: 2011-08-09 Created: 2011-08-09 Last updated: 2017-12-08Bibliographically approved
3. Mantle Cell Lymphoma is Characterized by a Strikingly Homogenous Methylation Profile: a comparative analysis with chronic lymphocytic leukemia
Open this publication in new window or tab >>Mantle Cell Lymphoma is Characterized by a Strikingly Homogenous Methylation Profile: a comparative analysis with chronic lymphocytic leukemia
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Article in journal (Refereed) Submitted
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156905 (URN)
Available from: 2011-08-11 Created: 2011-08-11 Last updated: 2017-12-08Bibliographically approved
4. Distinct global DNA methylation profiles among chronic lymphocytic leukemia subsets with stereotyped B cell receptors
Open this publication in new window or tab >>Distinct global DNA methylation profiles among chronic lymphocytic leukemia subsets with stereotyped B cell receptors
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-156906 (URN)
Available from: 2011-08-11 Created: 2011-08-11 Last updated: 2011-11-03

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