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Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
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, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.ORCID iD: 0000-0003-4450-0333
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
Division of Hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
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2014 (English)In: Biomarker Research, ISSN 2050-7771, Vol. 2, no 18Article in journal (Refereed) Published
Abstract [en]

The isocitrate dehydrogenase (IDH1/IDH2) genes are frequently mutated and reported to associate with poor prognosis in acute myeloid leukemia (AML). We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP  105C>T (rs11554137) in 207 unselected de novo AML patients. IDH1 codon 132 mutations were present in 7.7%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 10.1% and 2.9%, respectively. The SNP 105C>T was present in 10.1% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p=0.009) was observed in the intermediate risk patient group with cytogenetically normal karyotype (CN-AML). Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative CN-AML, (p=0.007). Our results indicate that IDH2 mutations and the IDH1 SNP 105C>T variant may represent a new subgroup for risk stratification and may indicate new treatment options.

Place, publisher, year, edition, pages
2014. Vol. 2, no 18
Keyword [en]
AML, IDH1, IDH2, SNP, prognostic markers
National Category
Clinical Medicine Medical Genetics
URN: urn:nbn:se:liu:diva-104949DOI: 10.1186/2050-7771-2-18OAI: diva2:700277
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2015-09-07Bibliographically approved
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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1393
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-104951 (URN)10.3384/diss.diva-104951 (DOI)978-91-7519-421-9 (print) (ISBN)
Public defence
2014-03-26, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2015-06-05Bibliographically approved

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Willander, KerstinJakobsen Falk, IngridChaireti, RozaGréen, HenrikLotfi, KouroshSöderkvist, PeterGreen, Henrik
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Division of Cell BiologyFaculty of Health SciencesDepartment of HaematologyDivision of Drug ResearchDivision of Microbiology and Molecular MedicineDepartment of Acute Internal MedicineDepartment of Clinical PharmacologyDepartment of Clinical Pathology and Clinical Genetics
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