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Tumkur Sitaram, Raviprakash
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Publications (10 of 18) Show all publications
Mallikarjuna, P., Tumkur Sitaram, R., Aripaka, K., Ljungberg, B. & Landström, M. (2019). Interactions between TGF-β type I receptor and hypoxia-inducible factor-alpha mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma. Cell Cycle, 18(17), 2141-2156
Open this publication in new window or tab >>Interactions between TGF-β type I receptor and hypoxia-inducible factor-alpha mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma
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2019 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 18, no 17, p. 2141-2156Article in journal (Refereed) Published
Abstract [en]

To investigate the significance of expression of HIF-1 alpha, HIF-2 alpha, and SNAIL1 proteins; and TGF-beta signaling pathway proteins in ccRCC, their relation with clinicopathological parameters and patient's survival were examined. We also investigated potential crosstalk between HIF-alpha and TGF-beta signaling pathway, including the TGF-beta type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD). Tissue samples from 154 ccRCC patients and comparable adjacent kidney cortex samples from 38 patients were analyzed for HIF-1 alpha/2 alpha, TGF-beta signaling components, and SNAIL1 proteins by immunoblot. Protein expression of HIF-1 alpha and HIF-2 alpha were significantly higher, while SNAIL1 had similar expression levels in ccRCC compared with the kidney cortex. HIF-2 alpha associated with poor cancer-specific survival, while HIF-1 alpha and SNAIL1 did not associate with survival. Moreover, HIF-2 alpha positively correlated with ALK5-ICD, pSMAD2/3, and PAI-1; HIF-1 alpha positively correlated with pSMAD2/3; SNAIL1 positively correlated with ALK5-FL, ALK5-ICD, pSMAD2/3, PAI-1, and HIF-2 alpha. Intriguingly, in vitro experiments performed under normoxic conditions revealed that ALK5 interacts with HIF-1 alpha and HIF-2 alpha, and promotes their expression and the expression of their target genes GLUT1 and CA9, in a VHL dependent manner. We found that ALK5 induces expression of HIF-1 alpha and HIF-2 alpha, through its kinase activity. Under hypoxic conditions, HIF-alpha proteins correlated with the activated TGF-beta signaling pathway. In conclusion, we reveal that ALK5 plays a pivotal role in synergistic crosstalk between TGF-beta signaling and hypoxia pathway, and that the interaction between ALK5 and HIF-alpha contributes to tumor progression.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
ALK5, clear cell renal cell carcinoma, HIF-α, SNAIL1, transforming growth factor-β
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-162654 (URN)10.1080/15384101.2019.1642069 (DOI)000478075700011 ()31339433 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-11-23Bibliographically approved
Laskar, R. S., Muller, D. C., Li, P., Machiela, M. J., Ye, Y., Gaborieau, V., . . . Scelo, G. (2019). Sex specific associations in genome wide association analysis of renal cell carcinoma. European Journal of Human Genetics, 27(10), 1589-1598
Open this publication in new window or tab >>Sex specific associations in genome wide association analysis of renal cell carcinoma
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 10, p. 1589-1598Article in journal (Refereed) Published
Abstract [en]

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-161383 (URN)10.1038/s41431-019-0455-9 (DOI)000485781600013 ()31231134 (PubMedID)
Available from: 2019-07-03 Created: 2019-07-03 Last updated: 2019-11-11Bibliographically approved
Johansson, M., Carreras-Torres, R., Scelo, G., Purdue, M. P., Mariosa, D., Muller, D. C., . . . Brennan, P. (2019). The influence of obesity-related factors in the etiology of renal cell carcinoma: A mendelian randomization study. PLoS Medicine, 16(1), Article ID e1002724.
Open this publication in new window or tab >>The influence of obesity-related factors in the etiology of renal cell carcinoma: A mendelian randomization study
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2019 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 1, article id e1002724Article in journal (Refereed) Published
Abstract [en]

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Place, publisher, year, edition, pages
Public Library of Science, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155372 (URN)10.1371/journal.pmed.1002724 (DOI)000457349900005 ()30605491 (PubMedID)2-s2.0-85059499698 (Scopus ID)
Funder
NIH (National Institute of Health), R01 CA170298
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-02-20Bibliographically approved
Mallikarjuna, P., Tumkur Sitaram, R., Landström, M. & Ljungberg, B. (2018). VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma. OncoTarget, 9(23), 16297-16310
Open this publication in new window or tab >>VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma
2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 23, p. 16297-16310Article in journal (Refereed) Published
Abstract [en]

To evaluate the role of pVHL in the regulation of TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC; the expression of pVHL, and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival were explored. Tissue samples from 143 ccRCC and 58 non-ccRCC patients were examined by immunoblot. ccRCC cell lines were utilized for mechanistic in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Non-ccRCC and ccRCC pVHL-High expressed similar levels of pVHL. Expression of the TGF-β type I receptor (ALK5) and intra-cellular domain were significantly higher in ccRCC compared with non-ccRCC. In non-ccRCC, expressions of ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 had no association with clinicopathological parameters and survival. In ccRCC pVHL-Low, ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 were significantly related with tumor stage, size, and survival. In ccRCC pVHL-High, the expression of PAI-1 was associated with stage and survival. In-vitro studies revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked poly-ubiquitination and proteasomal degradation, thus negatively controlling TGF-β induced cancer cell invasiveness. The pVHL status controls the ALK5 and can thereby regulate the TGF-β pathway, aggressiveness of tumors, and survival of the ccRCC and non-ccRCC patients.

Place, publisher, year, edition, pages
Impact Journals, LLC, 2018
Keywords
ccRCC, non-ccRCC, ALK5, pVHL, TGF-β signaling
National Category
Cancer and Oncology Cell and Molecular Biology
Research subject
molecular cell biology; Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-146504 (URN)10.18632/oncotarget.24631 (DOI)2-s2.0-85044474424 (Scopus ID)
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2019-11-23Bibliographically approved
Machiela, M. J., Hofmann, J. N., Carreras-Torres, R., Brown, K. M., Johansson, M., Wang, Z., . . . Purdue, M. P. (2017). Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma. European Urology, 72(5), 747-754
Open this publication in new window or tab >>Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma
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2017 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, no 5, p. 747-754Article in journal (Refereed) Published
Abstract [en]

Background: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.

Objective: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

Design, setting, and participants: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

Outcome measurements and statistical analysis: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.

Results and limitations: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR = 2.07 per predicted kilobase increase, 95% confidence interval [CI]: = 1.70-2.53, p < 0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R-2 > 0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR = 1.73, 95% CI = 1.36-2.21, p < 0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N = 5573, OR = 1.93, 95% CI = 1.50-2.49, p < 0.0001), papillary (N = 573, OR = 1.96, 95% CI = 1.01-3.81, p = 0.046), and chromophobe RCC (N = 203, OR = 2.37, 95% CI = 0.78-7.17, p = 0.13).

Conclusions: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.

Patient summary: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
renal cell carcinoma, telomere length, genetic variants, mendelian randomization, risk
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-142908 (URN)10.1016/j.eururo.2017.07.015 (DOI)000412685300027 ()28797570 (PubMedID)
Note

Correction to affiliations for authors Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Anush Mukeriya, Stefan Rascu, David Zaridze, Vladimir Bencko, and Cezary Cybulski in a corrected list, DOI: 10.1016/j.eururo.2018.05.017

Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2019-06-13Bibliographically approved
Scelo, G., Purdue, M. P., Brown, K. M., Johansson, M., Wang, Z., Eckel-Passow, J. E., . . . Chanock, S. J. (2017). Genome-wide association study identifies multiple risk loci for renal cell carcinoma. Nature Communications, 8, Article ID 15724.
Open this publication in new window or tab >>Genome-wide association study identifies multiple risk loci for renal cell carcinoma
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15724Article in journal (Refereed) Published
Abstract [en]

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P = 3.1 x 10(-10)), 3p22.1 (rs67311347, P = 2.5 x 10(-8)), 3q26.2 (rs10936602, P = 8.8 x 10(-9)), 8p21.3 (rs2241261, P = 5.8 x 10(-9)), 10q24.33-q25.1 (rs11813268, P = 3.9 x 10(-8)), 11q22.3 (rs74911261, P = 2.1 x 10(-10)) and 14q24.2 (rs4903064, P = 2.2 x 10(-24)). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-137038 (URN)10.1038/ncomms15724 (DOI)000402963900001 ()
Available from: 2017-06-28 Created: 2017-06-28 Last updated: 2018-06-09Bibliographically approved
Tumkur Sitaram, R., Mallikarjuna, P., Landström, M. & Ljungberg, B. (2016). Transforming growth factor-β promotes aggressiveness and invasion of clear cell renal cell carcinoma. OncoTarget, 7(24), 35917-35931
Open this publication in new window or tab >>Transforming growth factor-β promotes aggressiveness and invasion of clear cell renal cell carcinoma
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 35917-35931Article in journal (Refereed) Published
Abstract [en]

The molecular mechanisms whereby transforming growth factor-β (TGF-β) promotes clear cell renal cell carcinoma (ccRCC) progression is elusive. The cell membrane bound TGF-β type I receptor (ALK5), was recently found to undergo proteolytic cleavage in aggressive prostate cancer cells, resulting in liberation and subsequent nuclear translocation of its intracellular domain (ICD), suggesting that ALK5-ICD might be a useful cancer biomarker. Herein, the possible correlation between ALK5 full length (ALK5-FL) and ALK5-ICD protein, phosphorylated Smad2/3 (pSmad2/3), and expression of TGF-β target gene PAI-1, was investigated in a clinical ccRCC material, in relation to tumor grade, stage, size and cancer specific survival. Expression of ALK5-FL, ALK5-ICD, pSmad2/3 and PAI-1 protein levels were significantly higher in higher stage and associated with adverse survival. ALK5-ICD, pSmad2/3 and PAI-1 correlated with higher grade, and ALK5-FL, pSmad2/3 and PAI-1 protein levels were significantly correlated with larger tumor size. Moreover, the functional role of the TGF-β - ALK5-ICD pathway were investigated in two ccRCC cell lines by treatment with ADAM/MMP2 inhibitor TAPI-2, which prevented TGF-β-induced ALK5-ICD generation, nuclear translocation, as well as cell invasion. The present study demonstrated that canonical TGF-β Smad2/3 pathway and generation of ALK5-ICD correlates with poor survival and invasion of ccRCC in vitro.

Keywords
ccRCC, ALK5, pSmad2/3, PAI-1, TGF-β signaling pathway
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-120254 (URN)10.18632/oncotarget.9177 (DOI)000377756800034 ()27166254 (PubMedID)
Available from: 2016-05-12 Created: 2016-05-12 Last updated: 2019-11-23Bibliographically approved
Hosen, I., Rachakonda, P. S., Heidenreich, B., Sitaram, R. T., Ljungberg, B., Roos, G., . . . Kumar, R. (2015). TERT promoter mutations in clear cell renal cell carcinoma. International Journal of Cancer, 136(10), 2448-2452
Open this publication in new window or tab >>TERT promoter mutations in clear cell renal cell carcinoma
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2015 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 10, p. 2448-2452Article in journal (Refereed) Published
Abstract [en]

We screened promoter region of the telomerase reverse transcriptase (TERT) for activating somatic mutations in 188 tumors from patients with clear cell renal cell carcinoma (ccRCC). Twelve tumors (6.4%) carried a mutation within the core promoter region of the gene. The mutations were less frequent in high grade tumors compared to low grade tumors [odds ratio (OR)=0.15, 95% confidence interval (CI)=0.03-0.72, p=0.02]. Multivariate analysis for cause specific survival showed statistically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR)=2.90, 95% CI=1.13-7.39, p=0.03]. A common polymorphism (rs2853669) within the locus seemed to act as a modifier of the effect of the mutations on patient survival as the noncarriers of the variant allele with the TERT promoter mutations showed worst survival (HR=3.34, 95% CI=1.24-8.98, p=0.02). We also measured relative telomere length (RTL) in tumors and difference between tumors with and without the TERT promoter mutations was not statistically significant. Similarly, no difference in patient survival based on RTL in tumors was observed. Our study showed a relatively low frequency of TERT promoter mutations in ccRCC. Nevertheless, patients with the mutations, particularly in the absence of the rs2853669 variant showed the worst disease-specific survival. Thus, it is possible that the TERT promoter mutations define a small subset of tumors with an aggressive behavior. What's new? The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, a ribonucleoprotein complex that maintains genomic integrity. Activating somatic mutations in the promoter region of the TERT gene have been reported in many cancers. Here, the authors describe new TERT promoter mutations in clear cell renal cell carcinoma. Although present only in a proportion of the tumors, the TERT promoter mutations were independently associated with poor patient survival. The effect was enhanced by a common polymorphism within the core TERT promoter. The TERT promoter mutations may thus define a small subset of tumors with an aggressive behavior.

Keywords
TERT promoter mutations, telomere length, mutations, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-102191 (URN)10.1002/ijc.29279 (DOI)000351208300022 ()25331263 (PubMedID)
Available from: 2015-05-05 Created: 2015-04-22 Last updated: 2018-06-07Bibliographically approved
Jamshidi, N., Jonasch, E., Zapala, M., Korn, R. L., Aganovic, L., Zhao, H., . . . Kuo, M. D. (2015). The Radiogenomic Risk Score: construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma. Radiology, 277(1), 114-123
Open this publication in new window or tab >>The Radiogenomic Risk Score: construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma
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2015 (English)In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 277, no 1, p. 114-123Article in journal (Refereed) Published
Abstract [en]

Purpose: To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image.

Materials and Methods: In this institutional review board approved study, gene expression profile data and contrast material–enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression–based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis.

Results: Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57,P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001).

Conclusion: A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-116772 (URN)10.1148/radiol.2015150800 (DOI)000368434000014 ()26402495 (PubMedID)
Available from: 2016-02-12 Created: 2016-02-11 Last updated: 2018-06-07Bibliographically approved
Li, X., Wang, S., Sitaram, R. T., Andersson, C., Ljungberg, B. & Li, A.-H. (2013). Single Nucleotide Polymorphisms in the Wilms' Tumour Gene 1 in Clear Cell Renal Cell Carcinoma. PLoS ONE, 8(3), Article ID e58396.
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, article id 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: 2018-06-08Bibliographically approved
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