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Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology. (Molecular Haematology)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL.

In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL.

In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results.

In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 507
Keywords [en]
chronic lymphocytic leukemia, prognostic markers, single nucleotide polymorphisms, RNA-based markers
National Category
Medical Genetics Genetics Medical Genetics Biomedical Laboratory Science/Technology Cancer and Oncology Hematology
Research subject
Clinical Genetics; Molecular Medicine; Oncology; Medicine; Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-110371ISBN: 978-91-554-7677-9 (print)OAI: oai:DiVA.org:uu-110371DiVA, id: diva2:278818
Public defence
2010-01-20, Rudbecksalen, Rudbeck Laboratory C11, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2009-12-22 Created: 2009-11-12 Last updated: 2018-01-12Bibliographically approved
List of papers
1. The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia
Open this publication in new window or tab >>The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia
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2008 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 32, no 6, p. 984-987Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL.

Keywords
GNAS1 T393C single nucleotide polymorphism, chronic lymphocytic leukemia prognosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-13005 (URN)10.1016/j.leukres.2007.10.003 (DOI)000255269100021 ()18006055 (PubMedID)
Available from: 2008-01-20 Created: 2008-01-20 Last updated: 2017-12-11Bibliographically approved
2. The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia
Open this publication in new window or tab >>The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia
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2008 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 2, p. 339-343Article in journal (Refereed) Published
Abstract [en]

The (-938C>A) polymorphism in the promoter region of the BCL-2 gene was recently associated with inferior time to treatment and overall survival in B-cell chronic lymphocytic leukemia (CLL) patients displaying the -938A/A genotype and may thus serve as an unfavorable genetic marker in CLL. Furthermore, the -938A/A genotype was associated with increased expression of Bcl-2. To investigate this further, we analyzed the -938 genotypes of the BCL-2 gene in 268 CLL patients and correlated data with treatment status, overall survival and known prognostic factors, for example, Binet stage, immunoglobulin heavy-chain variable (IGHV) mutational status and CD38 expression. In contrast to the recent report, the current cohort of CLL patients showed no differences either in time to treatment or overall survival in relation to usage of a particular genotype. In addition, no correlation was evident between the (-938C>A) genotypes and IGHV mutational status, Binet stage or CD38. Furthermore, the polymorphism did not appear to affect the Bcl-2 expression at the RNA level. Taken together, our data do not support the use of the (-938C>A) BCL-2 polymorphism as a prognostic marker in CLL and argue against its postulated role in modulating Bcl-2 levels.

Keywords
chronic lymphocytic leukemia, BCL-2 promoter polymorphism, immunoglobulin heavy-chain variable gene mutation status, Binet stage, CD38, prognosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-13004 (URN)10.1038/sj.leu.2405042 (DOI)000253166900015 ()18046447 (PubMedID)
Available from: 2008-01-20 Created: 2009-01-12 Last updated: 2017-12-11Bibliographically approved
3. Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia
Open this publication in new window or tab >>Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia
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2010 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 3, p. 335-339Article in journal (Refereed) Published
Abstract [en]

The 309T>G polymorphism in the promoter region of the MDM2gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.

Keywords
MDM2 SNP309, Chronic lymphocytic leukemia, Binet stage, IGHV mutational status, Genomic aberrations, Prognostic markers
National Category
Medical and Health Sciences
Research subject
Clinical Genetics; Medicine; Oncology; Medical Genetics; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-111075 (URN)10.1016/j.leukres.2009.06.006 (DOI)000274529600013 ()19573916 (PubMedID)
Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2017-12-12Bibliographically approved
4. LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
Open this publication in new window or tab >>LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
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2011 (English)In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 96, no 8, p. 1153-1160Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers.

DESIGN AND METHODS:

Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.

RESULTS:

High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients.

CONCLUSIONS:

LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.

National Category
Medical and Health Sciences Medical Genetics Cancer and Oncology
Research subject
Clinical Genetics; Medical Genetics; Oncology
Identifiers
urn:nbn:se:uu:diva-111078 (URN)10.3324/haematol.2010.039396 (DOI)000294722700013 ()21508119 (PubMedID)
Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2018-01-12Bibliographically approved

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