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Prognostic Significance of Hypermethylation in the Promoter Region of the Wilms’ Tumour Gene 1 in Clear Cell Renal Cell Carcinoma
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-103388OAI: diva2:813031
Available from: 2015-05-21 Created: 2015-05-21 Last updated: 2015-05-21
In thesis
1. Wilms' tumor gene 1 in different types of cancer
Open this publication in new window or tab >>Wilms' tumor gene 1 in different types of cancer
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Wilms’ tumor gene 1 (WT1) was first reported as a tumor suppressor gene in Wilms’ tumor. However, later studies have shown the oncogenic properties of WT1 in a variety of tumors. It was recently proposed that WT1 was a chameleon gene, due to its dual functions in tumorigenesis. We aimed to investigate the clinical significance of WT1 as biomarker in acute myeloid leukemia (AML) and clear cell renal cell carcinoma (ccRCC) and to elucidate the function of WT1 as an oncogene in squamous cell carcinoma of head and neck (SCCHN).

In AML, it was suggested that WT1 expression was an applicable marker of minimal residual disease (MRD). In adult patients with AML, we found a good correlation between WT1 expression levels normalized to two control genes, β-actin and ABL. Outcome could be predicted by a reduction in WT1 expression in bone marrow (≥ 1-log) detected less than 1 month after diagnosis, when β-actin was used as control. Also, irrespective of the control gene used, outcome could be predicted by a reduction in WT1 expression in peripheral blood (≥ 2-log) detected between 1 and 6 months after treatment initiation.

Previous studies in RCC demonstrated that WT1 acted as a tumor suppressor. Thus, we tested whether single nucleotide polymorphisms (SNPs) or mutations in WT1 might be associated with WT1 expression and clinical outcome in patients with ccRCC. We performed sequencing analysis on 10 exons of the WT1 gene in a total of 182 patient samples, and we identified six different SNPs in the WT1 gene. We found that at least one or two copies of the minor allele were present in 61% of ccRCC tumor samples. However, no correlation was observed between WT1 SNP genotypes and RNA expression levels. Moreover, none of the previously reported WT1 mutations were found in ccRCC. Nevertheless, we found that a favorable outcome was associated the homozygous minor allele for WT1 SNP. We then further investigated whether WT1 methylation was related to WT1 expression and its clinical significance. Methylation array and pyrosequencing analyses showed that the WT1 promoter region CpG site, cg22975913, was the most frequently hypermethylated CpG site. We found a trend that showed nearly significant correlation between WT1 mRNA levels and hypermethylation in the 5’-untranslated region. Hypermethylation in the WT1 CpG site, cg22975913, was found to be associated with patient age and a worse prognosis.

One previous study reported that WT1 was overexpressed in SCCHN. That finding suggested that WT1 might play a role in oncogenesis. We found that both WT1 and p63 could promote cell proliferation. A positive correlation between WT1 and p63 expression was observed, and we identified p63 as a WT1 target gene. Furthermore, several known WT1 and p63 target genes were affected by knocking down WT1. Also, co-immunoprecipitation analyses demonstrated a protein interaction between WT1 and p53.

In summary, WT1 gene expression can provide useful information for MRD detection during treatment of patients with AML. In RCC, our results suggested that the prognostic impact of WT1 SNPs was limited to the subgroup of patients that were homozygous for the minor allele, and that WT1 promoter hypermethylation could be used as a prognostic biomarker. In SCCHN, WT1 and p63 acted as oncogenes by affecting multiple genes involved in cancer cell growth.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2015. 59 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1717
WT1, AML, MRD, ccRCC, SNPs, DNA methylation, SCCHN, p63
National Category
Cancer and Oncology
Research subject
Clinical Chemistry
urn:nbn:se:umu:diva-103389 (URN)978-91-7601-263-5 (ISBN)
Public defence
2015-06-12, Hörsal Betula, 6M, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2015-05-22 Created: 2015-05-21 Last updated: 2015-09-02Bibliographically approved

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Li, XingruAndersson-Evelönn, EmmaWang, SihanRaviprakash, Tumkur SitaramLandfors, MattiasOttosson, SofiaAndersson, CharlottaNilsson, SofieLjungberg, BörjeLi, Aihong
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