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Prognostic significance of specific anti-WT1 IgG antibody level in plasma in patients with ovarian carcinoma
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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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.

Place, publisher, year, edition, pages
2014. Vol. 3, no 4, 909-918 p.
Keyword [en]
Ovarian carcinoma, prognosis, WT1, WT1 IgG antibody
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-100163DOI: 10.1002/cam4.244ISI: 000348222300016PubMedID: 24715586OAI: oai:DiVA.org:umu-100163DiVA: diva2:790413
Available from: 2015-02-24 Created: 2015-02-24 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors
Open this publication in new window or tab >>Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors
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
Wilms’ tumor gene 1, biomarker, leukemia, renal cell carcinoma, ovarian carcinoma
National Category
Clinical Laboratory Medicine
Research subject
Clinical Chemistry; Pathology
Identifiers
urn:nbn:se:umu:diva-120912 (URN)978-91-7601-458-5 (ISBN)
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

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