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Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Wilms’ tumor gene 1 (WT1) is a zinc finger transcriptional regulator with crucial functions in embryonic development. Originally WT1 was described as a tumor suppressor gene, but later studies have shown oncogenic properties of WT1 in a variety of tumors. Because of its dual functions in tumorigenesis, WT1 has been described as a chameleon gene. In this thesis, the significance of WT1 as a biomarker was investigated in acute myeloid leukemia (AML), clear cell renal cell carcinoma (ccRCC), ovarian carcinoma (OC) and childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Previous studies have suggested that expression of WT1 is a potential marker for detection of minimal residual disease (MRD) in AML. We aimed to define expression of WT1 as an MRD marker in AML. In adult AML patients, we found that a reduction of WT1 expression in bone marrow (≥ 1-log) detected less than 1 month after diagnosis was associated with an improved overall survival (OS) and freedom from relapse (FFR). In peripheral blood, a reduction of WT1 expression (≥ 2-log) detected between 1 and 6 months after treatment initiation was associated with an improved OS and FFR.

WT1 harbor pathogenic genetic variants in a considerable proportion of AML and T-lymphoblastic leukemia (T-ALL), but mutations have not been reported in BCP-ALL. We aimed to evaluate the clinical impact of WT1 mutations and single nucleotide polymorphisms (SNPs) in BCP-ALL. Pathogenic mutations in the WT1 gene were rarely seen in childhood BCP-ALL. However, five WT1 SNPs were identified. In survival analyses, WT1 SNP rs1799925 was found to be associated with worse OS, indicating that WT1 SNP rs1799925 may be a useful marker for clinical outcome in childhood BCP-ALL. We also explored whether WT1 mutations and SNPs in ccRCC could be used as biomarkers for risk and treatment stratification. We therefore examined whether SNPs or mutations in WT1 were associated with WT1 expression and clinical outcome. Sequencing analysis revealed that none of the previously reported WT1 mutations were found in ccRCC; however, we identified six different WT1 SNPs. Our data suggest that pathogenic WT1 mutations are not involved in ccRCC, and the prognostic significance of WT1 SNPs in ccRCC is considerably weak. However, a favorable OS and disease-specific survival were found in the few cases harboring the homozygous minor allele.

OC has a poor prognosis, and early effective screening markers are lacking. Serous OCs are known to express the WT1 protein. Overexpressed oncogenic proteins can be considered potential candidate antigens for cancer vaccines and T-cell therapy. It was therefore of great interest to investigate whether anti-WT1 IgG antibody (Ab) measurements in plasma could serve as biomarkers of anti-OC response. We found limited prognostic impact, but the results indicated that anti-WT1 IgG Ab measurements in plasma and WT1 staining in tissue specimens could be potential biomarkers for patient outcome in the high-risk subtypes of OCs.

In conclusion, the results of this thesis indicate that WT1 gene expression can provide information about MRD of patients with AML, and WT1 SNP rs1799925 may be used as a biomarker for predicting clinical outcome in childhood BCP-ALL. In ccRCC, the prognostic significance of WT1 SNPs is weak and limited to the subgroup of patients that are homozygous for the minor allele. In OCs anti-WT1 IgG Ab measurement in plasma and WT1 staining in tissue specimens could possibly be used as biomarkers for predicting patient outcome in the high-risk subtypes of OCs.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 67 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1799
Keyword [en]
Wilms’ tumor gene 1, biomarker, leukemia, renal cell carcinoma, ovarian carcinoma
National Category
Clinical Laboratory Medicine
Research subject
Clinical Chemistry; Pathology
Identifiers
URN: urn:nbn:se:umu:diva-120912ISBN: 978-91-7601-458-5 (print)OAI: oai:DiVA.org:umu-120912DiVA: diva2:930382
Public defence
2016-06-15, Sal D, 9 tr., Tandläkarhögskolan, Norrlands universitetssjukhus (NUS), Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-25 Created: 2016-05-23 Last updated: 2016-05-26Bibliographically approved
List of papers
1. Reduction in WT1 Gene Expression During Early Treatment Predicts the Outcome in Patients With Acute Myeloid Leukemia
Open this publication in new window or tab >>Reduction in WT1 Gene Expression During Early Treatment Predicts the Outcome in Patients With Acute Myeloid Leukemia
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2012 (English)In: Diagnostic molecular pathology (Print), ISSN 1052-9551, E-ISSN 1533-4066, Vol. 21, no 4, 225-233 p.Article in journal (Refereed) Published
Abstract [en]

Wilms tumor gene 1 (WT1) expression has been suggested as an applicable minimal residual disease marker in acute myeloid leukemia (AML). We evaluated the use of this marker in 43 adult AML patients. Quantitative assessment of WT1 gene transcripts was performed using real-time quantitative-polymerase chain reaction assay. Samples from both the peripheral blood and the bone marrow were analyzed at diagnosis and during follow-up. A strong correlation was observed between WT1 normalized with 2 different control genes (beta-actin and ABL1, P < 0.001). WT1 mRNA level at diagnosis was of no prognostic relevance (P > 0.05). A >= 1-log reduction in WT1 expression in bone marrow samples taken < 1 month after diagnosis significantly correlated with an improved overall survival (P = 0.004) and freedom from relapse (P = 0.010) when beta-actin was used as control gene. Furthermore, a reduction in WT1 expression by >= 2 logs in peripheral blood samples taken at a later time point significantly correlated with a better outcome for overall survival (P = 0.004) and freedom from relapse (P = 0.012). This result was achieved when normalizing against both b-actin and ABL1. These results therefore suggest that WT1 gene expression can provide useful information for minimal residual disease detection in adult AML patients and that combined use of control genes can give more informative results.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2012
Keyword
WT1 gene expression, acute myeloid leukemia, minimal residual disease, RQ-PCR, control genes
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-62781 (URN)10.1097/PDM.0b013e318257ddb9 (DOI)000311221400005 ()
Available from: 2013-01-02 Created: 2012-12-18 Last updated: 2017-12-06Bibliographically approved
2. Single Nucleotide Polymorphisms in the Wilms' Tumour Gene 1 in Clear Cell Renal Cell Carcinoma
Open this publication in new window or tab >>Single Nucleotide Polymorphisms in the Wilms' Tumour Gene 1 in Clear Cell Renal Cell Carcinoma
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, e58396Article in journal (Refereed) Published
Abstract [en]

The Wilms' tumour gene 1 (WT1) single nucleotide polymorphism (SNP) rs16754 has recently been described as an independent prognostic factor in acute myeloid leukaemia (AML) patients. It is of great interest to test whether WT1 SNPs can be used as a molecular marker in other cancer types in order to improve risk and treatment stratification. We performed sequencing analysis on all 10 exons of the WT1 gene in a total of 182 patients with clear cell renal cell carcinoma (ccRCC). Six different SNPs were identified, in descending order for minor allele frequency: rs2234582, rs16754, rs1799925, rs5030315, rs2234583, and rs2234581. At least one minor allele for WT1 SNP was identified in 61% of ccRCC patients. In the entire study population, only 6% carried two copies of the minor allele. The genotypes of WT1 SNPs in 78 tumour-free kidney tissue specimens were found to be in 95% concordance with corresponding tumour samples. No correlation was observed between WT1 SNP genotypes and RNA expression level. WT1 SNP genotypes did not associate with clinical and pathological characteristics. We found favourable outcomes associated with the homozygous minor allele for WT1 SNP. However, SNP genotypes did not show to be of prognostic significance when comparing wild-type versus homozygous or heterozygous for the minor allele in the entire cohort. None of the previously reported WT1 mutations in AML was found in the present study. A novel WT1 missense mutation was identified in only one patient. Our data suggest that common WT1 mutations are not involved in ccRCC. Due to too few cases harbouring the homozygous minor allele, the prognostic impact needs to be verified in larger study populations.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-70351 (URN)10.1371/journal.pone.0058396 (DOI)000316936100116 ()
Available from: 2013-05-16 Created: 2013-05-14 Last updated: 2017-12-06Bibliographically approved
3. Prognostic significance of specific anti-WT1 IgG antibody level in plasma in patients with ovarian carcinoma
Open this publication in new window or tab >>Prognostic significance of specific anti-WT1 IgG antibody level in plasma in patients with ovarian carcinoma
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2014 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 4, 909-918 p.Article in journal (Refereed) Published
Abstract [en]

Ovarian carcinoma (OC) has a poor prognosis and lack early effective screening markers. Wilm's tumor gene 1 (WT1) is overexpressed in OCs. Therefore, it is of great interest to investigate whether WT1-specific antibody (Ab) measurements in plasma can serve as a biomarker of anti-OC response, and is of importance in relation to patient prognosis. Peripheral blood samples were obtained from a total of 103 women with ovarian tumors with median being 1 day (range 0-48 days) before operation. WT1 IgG Ab levels were evaluated using enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis of WT1 protein expression was performed on OC tissue samples. We found that low-WT1 Ab level in plasma was related to improved survival in patients diagnosed at stages III-IV and grade 3 carcinomas. Positive WT1 protein staining on OC tissue samples had a negative impact on survival in the entire cohort, both overall survival (OS) (P = 0.046) and progression-free survival (PFS) (P = 0.006), but not in the serous OC subtype. Combining WT1 IgG Ab levels and WT1 staining, patients with high-WT1 IgG Ab levels in plasma and positive WT1 protein staining in cancer tissues had shorter survival, with a significant association in PFS (P = 0.016). These results indicated that WT1 Ab measurements in plasma and WT1 staining in tissue specimens could be useful as biomarkers for patient outcome in the high-risk subtypes of OCs for postoperative individualized therapy.

Keyword
Ovarian carcinoma, prognosis, WT1, WT1 IgG antibody
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-100163 (URN)10.1002/cam4.244 (DOI)000348222300016 ()24715586 (PubMedID)
Available from: 2015-02-24 Created: 2015-02-24 Last updated: 2017-12-04Bibliographically approved
4. Analysis of single nucleotide polymorphisms and mutational status of Wilms' tumor gene 1 in childhood B-celll precursor acute lymphoblastic leukemia
Open this publication in new window or tab >>Analysis of single nucleotide polymorphisms and mutational status of Wilms' tumor gene 1 in childhood B-celll precursor acute lymphoblastic leukemia
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-120996 (URN)
Available from: 2016-05-24 Created: 2016-05-24 Last updated: 2016-05-24

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