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Sökning: WFRF:(Teh Bin Tean)

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1.
  • Bertolotto, Corine, et al. (författare)
  • A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
  • 2011
  • Ingår i: Nature. - Nature Publishing Group. - 0028-0836. ; 480:7375, s. 94-98
  • Tidskriftsartikel (refereegranskat)abstract
    • So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
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2.
  • Elgendy, Mohamed, et al. (författare)
  • Dual modulation of MCL-1 and mTOR determines the response to sunitinib
  • 2017
  • Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 127:1, s. 153-168
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.</p>
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3.
  • Laskar, Ruhina S, et al. (författare)
  • Sex specific associations in genome wide association analysis of renal cell carcinoma
  • 2019
  • Ingår i: European Journal of Human Genetics. - Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 27:10, s. 1589-1598
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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 (OR<sub>male</sub>) = 0.83 [95% CI = 0.78-0.89], P<sub>male</sub> = 1.71 × 10<sup>-8</sup> compared with female odds ratio (OR<sub>female</sub>) = 0.98 [95% CI = 0.90-1.07], P<sub>female</sub> = 0.68) and 12q23.3 (intergenic, OR<sub>male</sub> = 0.75 [95% CI = 0.68-0.83], P<sub>male</sub> = 1.59 × 10<sup>-8</sup> compared with OR<sub>female</sub> = 0.93 [95% CI = 0.82-1.06], P<sub>female</sub> = 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.</p>
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4.
  • Laskar, Ruhina S, et al. (författare)
  • Sex specific associations in genome wide association analysis of renal cell carcinoma.
  • 2019
  • Ingår i: European Journal of Human Genetics. - 1018-4813 .- 1476-5438. ; 27:10, s. 1589-1598
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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 (OR<sub>male</sub>) = 0.83 [95% CI = 0.78-0.89], P<sub>male</sub> = 1.71 × 10<sup>-8</sup> compared with female odds ratio (OR<sub>female</sub>) = 0.98 [95% CI = 0.90-1.07], P<sub>female</sub> = 0.68) and 12q23.3 (intergenic, OR<sub>male</sub> = 0.75 [95% CI = 0.68-0.83], P<sub>male</sub> = 1.59 × 10<sup>-8</sup> compared with OR<sub>female</sub> = 0.93 [95% CI = 0.82-1.06], P<sub>female</sub> = 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.</p>
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5.
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6.
  • Machiela, Mitchell J., et al. (författare)
  • Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma
  • 2017
  • Ingår i: European Urology. - Elsevier. - 0302-2838 .- 1873-7560. ; 72:5, s. 747-754
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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 &lt; 0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R-2 &gt; 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 &lt; 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 &lt; 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).</p><p>Conclusions: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.</p><p>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.</p>
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7.
  • Machiela, Mitchell J, et al. (författare)
  • Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
  • 2017
  • Ingår i: European Urology. - 0302-2838 .- 1873-7560. ; 72:5, s. 747-754
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>BACKGROUND:</strong> 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.</p><p><strong>OBJECTIVE:</strong> 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.</p><p><strong>DESIGN, SETTING, AND PARTICIPANTS:</strong> 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.</p><p><strong>OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:</strong> Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.</p><p><strong>RESULTS AND LIMITATIONS:</strong> 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&lt;0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2&gt;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&lt;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&lt;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).</p><p><strong>CONCLUSIONS:</strong> Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.</p><p><strong>PATIENT SUMMARY:</strong> 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.</p>
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8.
  • Rosén, Anders, et al. (författare)
  • Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection
  • 2012
  • Ingår i: Oncoimmunology. - 2162-4011. ; 1:1, s. 18-27
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1-2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16-1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (&gt; 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.</p>
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9.
  • Rosén, Anders, et al. (författare)
  • Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection
  • 2012
  • Ingår i: OncoImmunology. - Landes Biosciences. - 2162-402X. ; 1:1, s. 18-27
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an <em>IGHV1–2</em> unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of <em>DLEU7</em>, miR15a/miR16–1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (<em>cf</em>. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (&gt; 2-fold). Among these were <em>LHX2</em> and <em>LILRA.</em> These genes may play a role in the development of the disease. <em>LHX2</em> expression was shown in self-renewing multipotent hematopoietic stem cells, and <em>LILRA4</em> codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these <em>PARD3</em> that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.</p>
10.
  • Scelo, Ghislaine, et al. (författare)
  • Genome-wide association study identifies multiple risk loci for renal cell carcinoma
  • 2017
  • Ingår i: Nature Communications. - NATURE PUBLISHING GROUP. - 2041-1723 .- 2041-1723. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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.</p>
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