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LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Molecular Haematology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Molecular Haematology)
Department of Hematology, Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Molecular Haematology)
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2011 (English)In: Haematologica (online), ISSN 1592-8721, Vol. 96, no 8, 1153-1160 p.Article 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.

Place, publisher, year, edition, pages
2011. Vol. 96, no 8, 1153-1160 p.
National Category
Medical and Health Sciences Medical Genetics Cancer and Oncology
Research subject
Clinical Genetics; Medical Genetics; Oncology
Identifiers
URN: urn:nbn:se:uu:diva-111078DOI: 10.3324/haematol.2010.039396ISI: 000294722700013PubMedID: 21508119OAI: oai:DiVA.org:uu-111078DiVA: diva2:279315
Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2012-03-12Bibliographically approved
In thesis
1. Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
Open this publication in new window or tab >>Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
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. 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 507
Keyword
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:nbn:se:uu:diva-110371 (URN)978-91-554-7677-9 (ISBN)
Public defence
2010-01-20, Rudbecksalen, Rudbeck Laboratory C11, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
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Available from: 2009-12-22 Created: 2009-11-12 Last updated: 2011-03-04Bibliographically approved

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Kaderi, Mohd ArifinKanduri, MeenaSevov, MarieCahill, NicolaJansson, MattiasMansouri, LarryRosenquist, Richard

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