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NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Lund University, Sweden.
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2013 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13Article in journal (Refereed) Published
Abstract [en]

Background

NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.

Methods

In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.

Results

In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).

Conclusions

Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.

Place, publisher, year, edition, pages
BioMed Central , 2013. Vol. 13
Keyword [en]
Chronic lymphocytic leukemia; NOTCH1 mutations; TP53 mutations; Prognostic markers
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-96472DOI: 10.1186/1471-2407-13-274ISI: 000319998800001OAI: oai:DiVA.org:liu-96472DiVA: diva2:642902
Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2017-12-06
In thesis
1. Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers
Open this publication in new window or tab >>Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present thesis is focused on the prognostic value of genetic variations and alterations in the initiation and development of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) patients. Several prognostic markers based on genetic or chromosomal aberrations are today used in clinic in these heterogeneous diseases. Novel biomarkers have been identified through next generation sequencing techniques and some of them may be useful as prognostic markers in clinical diagnostic. In papers I-IV we have investigated some of this markers in CLL and AML tumor cells.

In papers I and III we investigated the prognostic value of the MDM2 SNP309 in relation to the presence of TP53 mutations in tumor cells from CLL and AML patients. The SNP309 G-allele was associated with a shorter overall survival in TP53 wildtype CLL and non-normal karyotype AML patients. Mutations in the TP53 gene were found in 6.2% in CLL and 21.7% in AML and were always associated with adverse overall survival. This was most significant observed among the AML patients, where the three year survival was zero.

In paper II we investigated mutations in NOTCH1 and NOTCH2 as prognostic biomarkers in CLL. Notch1 and Notch2 play critical roles in lineage differentiation of white blood cells. We found mutation only in NOTCH1 in a frequency of 6.7% and our analysis revealed a shorter overall survival for these. NOTCH1 mutations were almost mutually exclusive with TP53 mutations and represented together 12.9% in CLL patients, and they may both be strong prognostic biomarkers in CLL.

In paper IV we studied mutations in the tricarboxylic acid cycle. Metabolic disturbances in cancer cells have been known for many years, but recently mechanistic explanations have been identified. Hot spot mutations in IDH1/2 genes, result in neomorphic enzyme activities that results in global hypermethylation of the cancer cell genome. We found mutations in 21% of the AML patients. Among the CN-AML patients there is a lack of prognostic markers and in this subgroup we found patients with IDH2 mutations to have a shorter overall survival (3 vs. 21 months (p=0.009) for mutated and wild-type patients, respectively). Additionally, we also studied a SNP in the IDH1 gene, and both the IDH2 mutations and the SNP showed to have a potential as a new prognostic markers in CN-AML.

In summary, the results in papers I-IV have a potential to function as novel prognostic biomarkers in the clinic for therapeutic considerations and may also be targets for novel drugs for CLL and AML patients.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 59 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1393
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104951 (URN)10.3384/diss.diva-104951 (DOI)978-91-7519-421-9 (ISBN)
Public defence
2014-03-26, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2015-06-05Bibliographically approved

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Willander, KerstinKumar Dutta, RaviUngerbäck, JonasFredrikson, MatsSöderkvist, Peter

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Willander, KerstinKumar Dutta, RaviUngerbäck, JonasFredrikson, MatsSöderkvist, Peter
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