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Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers
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.
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: urn:nbn:se:liu:diva-104951DOI: 10.3384/diss.diva-104951ISBN: 978-91-7519-421-9 (print)OAI: oai:DiVA.org:liu-104951DiVA: diva2:700322
Public defence
2014-03-26, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2015-06-05Bibliographically approved
List of papers
1. MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia
Open this publication in new window or tab >>MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia
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2010 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 85, no 3, 251-256 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The single nucleotide polymorphism SNP309 with a change from T to G in the promoter region of the MDM2 gene is shown to increase the MDM2 protein levels and attenuate the p53 levels and associates with disease progression in several tumors. OBJECTIVE: In this study, the role of the polymorphism was investigated with regard to the clinical outcome in B-cell chronic lymphocytic leukemia (B-CLL). PATIENTS: A total of 210 patients with B-CLL were followed for up to 19 yr. RESULTS: The overall survival (OS) of patients with at least one G-allele was significantly shorter when compared with those with two T-alleles (P = 0.024) with a more pronounced difference in patients below the median age. Age at onset of B-CLL was similar irrespective of MDM2 status. The presence of a G-allele in combination with TP53 mutations or unmutated IgVH gene status resulted in an additive risk of death. CONCLUSION: In this report, with a high proportion of B-CLL patients with an advanced Binet stage and with an unmutated IgVH gene, MDM2 SNP309 was found to be independently associated with OS. The survival difference was more pronounced in younger patients.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58806 (URN)10.1111/j.1600-0609.2010.01470.x (DOI)000280996400010 ()20491880 (PubMedID)
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12
2. NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients
Open this publication in new window or tab >>NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients
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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
Keyword
Chronic lymphocytic leukemia; NOTCH1 mutations; TP53 mutations; Prognostic markers
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96472 (URN)10.1186/1471-2407-13-274 (DOI)000319998800001 ()
Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2017-12-06
3. TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome
Open this publication in new window or tab >>TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of MDM2 (mouse double minute 2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment outcome and overall survival (OS) in 207 Swedish AML patients. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p<0.001). TP53mut patients had lower response rates compared to TP53 wild-type (wt) patients (22% and 76% CR, respectively, p<0.001) and reduced OS (5 and 21 months, respectively, p<0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele  having shorter OS compared to T/T patients (13 and 29 months, p=0.031). In conclusion, our results show that TP53mut analysis as well as MDM2SNP309 genotyping may be useful tools for prognostication, risk stratification and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

Keyword
AML, TP53, MDM2, SNP309, prognostic markers
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-104948 (URN)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2015-04-14Bibliographically approved
4. Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
Open this publication in new window or tab >>Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
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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.

Keyword
AML, IDH1, IDH2, SNP, prognostic markers
National Category
Clinical Medicine Medical Genetics
Identifiers
urn:nbn:se:liu:diva-104949 (URN)10.1186/2050-7771-2-18 (DOI)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-10-22Bibliographically approved

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