Development Of Renal Cell Cancer Research Articles

Hypoxia contributes to galectin-3 expression in renal carcinoma cells

Galectin-3 is supposed as a prognostic factor and therapeutic target for many cancers. In a previous study, we have reported that galectin-3 was related to the development of renal cell cancer and served a therapeutic target for renal cell carcinoma (RCC). However, the mechanisms underlying the regulation of galectin-3 in RCC are still not known. In this study, we detected the expression of galectin-3 and hypoxia-inducible factor 1 (HIF-1) α in RCC using immunohistochemistry, and then conducted in vitro experiments to verify the regulation of galectin-3 by hypoxia in RCC. Our results showed that the expression of galectin-3 and HIF-1α were remarkably high in RCC tissues compared with those in the paracancerous tissues. Interestingly, hypoxia significantly promoted cytoplasmic and nuclear HIF-1α and galectin-3 expression in renal carcinoma cell lines, but not in renal tubular epithelial cell (HK-2). Renal carcinoma cell line (Caki-1), but not HK-2 showed significant increase of luciferase reporter activity of galectin-3 encoding the fragment from the site of −845 to +50 upon hypoxic insult. Moreover, HIF-1α overexpression vector promoted, while HIF-1α silencing vector reduced luciferase reporter activity of galectin-3 in Caki-1 and HK-2 cells in both normal and hypoxia conditions. A direct interaction of HIF-1α with Gal-3 promoter was also verified by electrophoretic mobility shift assay and chromatin immunoprecipitation. Together, our data indicated that hypoxia was critical for galectin-3 expression in RCC in a HIF-1α-dependent manner.

From oxygen sensing to angiogenesis: Targeting the hypoxia signaling pathway in metastatic kidney cancer.

This article summarizes examples of current and emerging therapies that target the hypoxia and angiogenesis signaling pathways in the clear cell type of renal cell cancer (RCC), with an emphasis on the hypoxia signaling pathway. Mammalian cells transduce signals of decreased oxygen to hypoxia inducible factor (HIF), an intracellular heterodimer that mediates the adaptation of normal and tumor cells to oxygen deprivation. HIF is frequently overexpressed in cancer cells and is involved in the transcriptional activation of many genes essential for cell invasion, migration, survival, and angiogenesis (including vascular endothelial growth factor [VEGF]). Moreover, HIF confers resistance to cytotoxic chemotherapy and radiation therapy and is associated with poor prognosis in patients with cancer. Blocking the activity of HIF inhibits the expression of VEGF and oncogenic pathways, resulting in the inhibition of tumor growth. Interestingly, activation of oncogenes and/or inactivation of tumor suppressor genes (eg, the gene encoding von Hippel-Lindau [VHL] tumor suppressor protein) can activate tumorigenesis even with normal levels of oxygen, providing support for the notion that the HIF-VHL-VEGF axis is amenable to targeted therapies for the treatment of RCC. This article highlights the current understanding of the hypoxia signaling pathway and its relevance to RCC development. Pharmacologic agents targeting the hypoxia and angiogenesis signaling pathways are discussed. Development of novel therapeutic agents that target the hypoxia and angiogenesis signaling pathways holds promise in the management of metastatic clear cell RCC.

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets.

Renal cell cancer (RCC) involves three most recurrent sporadic types: clear-cell RCC (70–75%, CCRCC), papillary RCCC (10–15%, PRCC), and chromophobe RCC (5%, CHRCC). Hereditary cases account for about 5% of all cases of RCC and are caused by germline pathogenic variants. Herein, we review how a better understanding of the molecular biology of RCCs has driven the inception of new diagnostic and therapeutic approaches. Genomic research has identified relevant genetic alterations associated with each RCC subtype. Molecular studies have clearly shown that CCRCC is universally initiated by Von Hippel Lindau (VHL) gene dysregulation, followed by different types of additional genetic events involving epigenetic regulatory genes, dictating disease progression, aggressiveness, and differential response to treatments. The understanding of the molecular mechanisms that underlie the development and progression of RCC has considerably expanded treatment options; genomic data might guide treatment options by enabling patients to be matched with therapeutics that specifically target the genetic alterations present in their tumors. These new targeted treatments have led to a moderate improvement of the survival of metastatic RCC patients. Ongoing studies based on the combination of immunotherapeutic agents (immune check inhibitors) with VEGF inhibitors are expected to further improve the survival of these patients.

Age-, tumor-, and metastatic tissue-associated DNA hypermethylation of a T-box brain 1 locus in human kidney tissue

BackgroundWhile a considerable number of tumor-specific hypermethylated loci have been identified in renal cell cancer (RCC), DNA methylation of loci showing successive increases in normal, tumoral, and metastatic tissues could point to genes with high relevance both for the process of tumor development and progression. Here, we report that DNA methylation of a locus in a genomic region corresponding to the 3′UTR of the transcription factor T-box brain 1 (TBR1) mRNA accumulates in normal renal tissues with age and possibly increased body mass index. Moreover, a further tissue-specific increase of methylation was observed for tumor and metastatic tissue samples.ResultsBiometric analyses of the TCGA KIRC methylation data revealed candidate loci for age-dependent and tumor-specific DNA methylation within the last exon and in a genomic region corresponding to the 3′UTR TBR1 mRNA. To evaluate whether methylation of TBR1 shows association with RCC carcinogenesis, we measured 15 tumor cell lines and 907 renal tissue samples including 355 normal tissues, 175 tissue pairs of normal tumor adjacent and corresponding tumor tissue as well 202 metastatic tissues samples of lung, bone, and brain metastases by the use of pyrosequencing. Statistical evaluation demonstrated age-dependent methylation in normal tissue (R = 0.72, p < 2 × 10−16), association with adiposity (P = 0.019) and tumor-specific hypermethylation (P = 6.1 × 10−19) for RCC tissues. Comparison of tumor and metastatic tissues revealed higher methylation in renal cancer metastases (P = 2.65 × 10−6).ConclusionsOur analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.

Long noncoding RNA ZFPM2-AS1 promotes the tumorigenesis of renal cell cancer via targeting miR-137.

Recently, long noncoding RNAs (lncRNAs) have attracted more attention for their roles in tumor progression. The aim of this study was to investigate the role of lncRNA ZFPM2 antisense RNA 1 (ZFPM2-AS1) in the progression of renal cell cancer (RCC), and to explore the possible underlying mechanism. Expression levels of ZFPM2-AS1 in both RCC cells and 50 paired tissue samples were detected by Real Time-quantitative Polymerase Chain Reaction (RT-qPCR). Moreover, the relationship between lncRNA ZFPM2-AS1 expression level and clinic-pathological characteristics as well as patients' disease-free survival rate was explored, respectively. Furthermore, cell proliferation assay, wound healing assay and transwell assay were performed to investigate the role of lncRNA ZFPM2-AS1 in vitro. In addition, Western blot assay, Luciferase reporter gene assay and RNA immunoprecipitation assay were used to explore the possible underlying mechanism. The expression level of ZFPM2-AS1 in tumor tissues was significantly higher than that of corresponding normal tissues. ZFPM2-AS1 expression was associated with lymph node metastasis, tumor stage and survival time of RCC patients. Moreover, the overexpression of ZFPM2-AS1 significantly promoted the growth, invasion and migration of tumor cells, whereas remarkably inhibited cell apoptosis in vitro. Further experiments revealed that miR-137 was a direct target of ZFPM2-AS1. In addition, miR-137 expression in tumor tissues was negatively correlated with ZFPM2-AS1 expression. Our findings indicated that ZFPM2-AS1 could promote metastasis and proliferation, whereas inhibiting the apoptosis of RCC via targeting miR-137. This study might provide a new vision for interpreting the mechanism of RCC development.

MiR-1-3p suppresses the epithelial-mesenchymal transition property in renal cell cancer by downregulating Fibronectin 1.

PurposeRenal cell cancer (RCC) is one of the primary causes of malignancy deaths all over the world. The most important cause of RCC-related mortality is metastasis. Epithelial-mesenchymal transition (EMT) plays an important role in metastasis of malignant tumors including RCC. miR-1-3p is confirmed to be decreased in many types of cancer. Nevertheless, the function of miR-1-3p in RCC metastasis and EMT process was still unclear.Materials and methodsIn this study, information from clinical investigation, in vitro study, and in vivo study discovered miR-1-3p expression character and its status in RCC. The character of miR-1-3p in invasive and metastatic properties in vitro and in vivo was also inspected in RCC cells and xenograft tumor model, and expression levels of EMT markers were evaluated in RCC cells and tissues.ResultsmiR-1-3p was proved to be decreased in RCC cell lines and tissues compared with normal renal cells and tissues. miR-1-3p expression level in RCC tissues was closely related with capsulation, lymph node metastasis, and vascular invasion. miR-1-3p was found to be able to block the EMT process in A498 and CAKI-1 RCC cells and tumors. Luciferase reporter assay and expression level rescue assays were employed to reveal that miR-1-3p inhibited the invasion and migration property of RCC cells by directly targeting Fibronectin 1. Upregulation of Fibronectin 1 partially reversed the suppressive effect of miR-1-3p on EMT process.ConclusionIn brief, this study has verified that miR-1-3p blocked the EMT process of RCC cells by reducing Fibronectin 1 expression. miR-1-3p/Fibronectin 1 axis may be considered as a new target for drug development of RCC.

MicroRNAs (miRNAs) as predictors of extreme response to tyrosine kinase inhibitors in renal cell cancer (RCC).

e16076 Background: A number of different drugs are approved for the 1stline treatment of mRCC and provide a median PFS of ≈ 11 months. Yet, a small subset of pts will present an unusually either short or prolong response [extreme responders]. MiRNAs are small fragments of RNA that modulate gene expression controlling cell development and differentiation. Promising results about their value as predictors of drug response have been published in lung and colorectal cancer [Molina-Pinelo]. This study aims to define miRNA profiles in RCC and determine whether they can predict “extreme responses”. Methods: The expression of 754 miRNAs was analyzed with TaqMan Low Density Array Human MicroRNA Panel (TLDA) (ThermoFisher). QPCR was carried out in the System of Gene Expression and Genotyping Arrays module ViiA7. We defined long-term response pts (LR) (PFS˃11 months, n = 7) and primary refractory pts (PR) (progression as best response, n = 8). MiRNAs differentially expressed were independently analyzed by individual qPCR assays in the study cohort and in an external validation cohort of pts (n = 35). Statistical analysis was performed with SPSSv20. Results: Four miRNAs were significantly associated with patient response and differentially expressed in PR vs LR (up-regulated in PR: miR-425-5p, down-regulated in PR: miR-139-3p, let-7d and let-7e). Let-7d and let-7e were validated internally (p &lt; 0.05) and all of them showed the same tendency but without statistically significance in the external validation cohort. Fourteen miRNAs had differential expression in tumor vs healthy tissue and seven were validated in the study cohort (tumor up-regulated: miR-146b, miR-21, miR-155, miR-122; tumor down-regulated: miR-135a, miR-200c and miR-187). When externally validated four (miR-135a, miR-200c, miR-187 and miR-21) (p &lt; 0.05) were confirmed. Conclusions: MiRNAs could represent a valid predictive biomarker in the development of RCC and its treatment. These results have been validated in an independent cohort. MiRNAs regulation in PR vs LR patients need to continue being validated in a more extensive cohort of pts.

Renal Tumor in Allogeneic Kidney Transplant Recipient

BackgroundMalignancies will be a leading cause of mortality in renal transplant recipients in the next 20 years. Renal cell cancer (RCC) is the most common urologic cancer in kidney transplant recipients. The risk of RCC development in kidney transplant recipients is 15–100 times higher than in the general population. The purpose of the current retrospective study was to assess the frequency of nephrectomies performed because of renal tumors in the native kidneys in kidney transplant recipients in the Department of General and Transplantation Surgery at the Medical University of Warsaw between 2010 and 2014 year; the identification of kidney recipients diagnosed with RCC; and epidemiologic, clinical, and histopathological aspects associated with RCC. Patients and MethodsA total of 319 nephrectomies were performed in the Department of General and Transplantation Surgery at the Medical University of Warsaw between 2010 and 2014 year. Renal tumors were diagnosed in 25 renal transplant recipients. ResultsAmong malignant tumors, 13 cases of RCC and 1 case of post-transplant lymphoproliferative disorder (PTLD) were observed. There was no significant difference between age and duration of pretransplantation dialysis in patients with RCC and patients with benign tumors (P = .14 and P = .91, respectively). Body mass index was significantly higher in patients with RCC than in patients with benign tumors (P = .04). ConclusionsRenal cell cancer is more common among male kidney recipients. There is a good Polish screening system allowing detection of kidney cancer in native kidney. We recommend performing periodic screening for kidney cancers to obtain an early diagnosis.

Antitumor effects of galectin-3 inhibition in human renal carcinoma cells.

Galectins are thought to be prognosticators for survival in renal cell cancer. However, the biological activity of galectin-3 (Gal-3) in renal carcinoma cells is still debated. In this study, immunohistochemical staining confirmed a high expression of Gal-3 in tumor tissue from renal cell carcinoma. Critically, Gal-3 expression was related to tumor cell differentiation. Consistent with Gal-3 expression in renal cell cancer, strong expression of Gal-3 was also observed in several renal tumor cell lines but not in normal renal cells. A Gal-3 high-expression cell line Caki-1 was chosen to study the biological activity of Gal-3. Using short hairpin RNA method, Gal-3 expression in Caki-1 cells was knocked down. We evidenced that Gal-3 knockdown inhibited cell proliferation and invasion, induced Caspase-3-dependent apoptosis and arrested cell cycle at G1 phase. Mechanically, Cyclin D1 expression decreased, but p27 increased after Gal-3 knockdown. Taken together, these results suggest that Gal-3 is related to the development of renal cell cancer and could serve as a target to therapy renal cell cancer.

IL-16 rs4778889 polymorphism contribution to the development of renal cell cancer in a Chinese population.

IL-16 plays an important role in affect the secretion of tumor-related inflammatory cytokines. We aimed to assess the role of interleukin-16 (IL-16) rs4778889 T/C and rs11556218 T/G polymorphisms in the occurrence of renal cell cancer (RCC). This study is composed of 274 RCC patients and 274 control subjects. Genotyping of polymorphisms was performed using polymerase chain reaction combined with restriction fragment length polymorphism analysis. All statistical analysis was carried out by the SPSS statistical software package, version 16.0 (SPSS Inc., Chicago, IL, USA). Using conditional logistic regression analysis, the TC and CC genotypes of rs4778889 exhibited a higher risk of RCC, with adjusted ORs (and 95%CIs) of 1.79 (1.23-2.62) and 2.67 (1.29-5.69), respectively. Moreover, under dominant and recessive models, individuals carried the rs4778889 polymorphism was exhibited elevated RCC risk, with adjusted ORs (and 95%CI) of 1.93 (1.35-2.76) and 2.11 (1.05-4.45), respectively. No significant differences were observed in rs11556218 genotype frequencies between the study groups. In conclusion, the results of our study reveal an association between the IL-16 rs4778889 polymorphism and heightened risk of RCC.

Abstract 883: Body mass, smoking habit, and hypertension and renal cell cancer survival

Abstract Background: A recent meta-analysis showed higher survival rate among over-weight and obese renal cell cancer (RCC) patients. Given that obesity, smoking and hypertension are well-established risk factors for RCC development, it is therefore important to know whether these factors are associated with RCC prognosis. Objectives: We evaluated the associations of body mass index (BMI), smoking and hypertension with RCC survival in a population-based cohort of incident RCC cases assembled from a Swedish case-control study. Methods: We analyzed a total of 371 RCC cases diagnosed in 1988-1992 with follow-up through Dec 31, 2011. Information on weight, height, smoking habit and hypertension was obtained through face-to-face interviews. Mortality information was determined through linkage to the National Cancer Registry; 298 deaths were identified, with 148 of those having RCC as the underlying cause of death, during an average of 9.9 years of follow-up. We calculated hazard ratios (HR)s and 95% confidence interval (CI)s using the Cox proportional hazards models. Results: We confirmed that lifetime smoking and BMI at highest adult weight were associated with a worse overall survival among RCC patients. When we examined RCC-specific survival, the associations were not statistically significant; multivariate HR (95% CI) was 0.89 (0.54-1.49) for 20 or greater pack-years of smoking compared to never smokers. For BMI at highest adult weight, multivariate HR (95% CI) was 0.99 (0.53-1.87) comparing 35 or greater levels of BMI with less than 27 kg/m2 of BMI. History of hypertension was not associated with overall or RCC-specific survival. Conclusions: We found a decreasing trend of overall survival with increasing prediagnostic BMI and lifetime smoking, but no significant associations of these factors and hypertension with RCC-specific survival among RCC patients. Citation Format: Jung Eun Lee, Nayeon Kim, Hans-Olov Adami, Per Lindblad. Body mass, smoking habit, and hypertension and renal cell cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 883. doi:10.1158/1538-7445.AM2015-883

Renal Cell Cancer in a European Regional Renal Transplant Population: Is There a Role for Immediate Native Renal Radiological Surveillance Before and After Transplantation?

BackgroundThe risk of the development of renal cell cancer (RCC) in renal transplant recipients is several times higher than the general population. There can often be a delay between initial radiological imaging and patients undergoing renal transplantation. We present and evaluate the prevalence and clinical characteristics of RCC in renal transplant recipients at a single UK transplant center, with particular focus on tumors diagnosed in the immediate post-operative period, that is, likely present before transplantation. MethodsThis is a retrospective cohort study examining all renal transplant recipients with the diagnosis of RCC of native and/or graft kidneys followed up in a single UK transplant center. ResultsBetween January 2002 and April 2014, 1386 patients underwent renal transplantation. 19 of 1386 patients had development of RCC (1.4%): 17 native and 2 graft tumors. The mean interval between pre-operative native renal imaging and transplantation was 3.5 years in 13 of 19 patients (range, 1–10 years). Six patients had no documented renal imaging before their renal transplant. The median time from transplantation to diagnosis of RCC was 5 years (range, 1 month to 30 years). In 5 patients (26.3%), RSS developed within 6 months of undergoing renal transplantation. ConclusionsIn our study, we identified several patients with RCC diagnosed shortly after surgery, which raised the possibility that this was present before transplantation. With transplant recipients at increased risk of development of RCC and early detection key in the management of RCC, there appears to be a role for native renal radiological screening for patients undergoing renal transplantation.

The role of prostaglandin E2 in renal cell cancer development: future implications for prognosis and therapy.

COX-2 plays a crucial pathophysiological role in the development of renal cell cancer (RCC). Recently, it has been shown that COX-2 inhibition enhances the efficacy of immunotherapy and tyrosine kinase inhibitor-based treatment. At the same time, molecular analyses revealed particular contribution of a COX-2 product - prostaglandin E2 (PGE2) - in RCC development. PGE2 was shown to activate Akt/RGC2/RalA signaling cascade in RCC cells. It also demonstrated upregulation of the expression of HIF-1α and PI3K/Akt/mTOR signaling pathway. All together, these data suggest that targeted anti-PGE2 therapies may offer an interesting therapeutic option for RCC patients in the future.

Vitamin D receptor gene polymorphisms in breast and renal cancer: Current state and future approaches

Cancer is a major health problem and cause of death worldwide that accounted for 7.6 million deaths in 2008, which is projected to continue rising with an estimated 13.1 million deaths in 2030 according to WHO. Breast cancer is the leading cause of cancer-based death among women around the world and its incidence is increasing annually with a similar tendency. In contrast, renal cell carcinoma accounts for only 3% of total human malignancies but it is still the most common type of urological cancer with a high prevalence in elderly men (>60 years of age). There are several factors linked with the development of renal cell cancer only, while others are connected only with breast cancer. Genetic risk factors and smoking are the factors which contribute to carcinogenesis in general. Some evidence exists indicating that vitamin D receptor (VDR) gene polymorphisms are associated with both breast and renal cancer; therefore, we put forward the hypothesis that polymorphisms in the VDR gene may influence both the occurrence risks of these cancers and their prognosis. However, the relationship between VDR polymorphisms and these two specific cancers remains a controversial hypothesis, and consequently needs further confirmation via clinical research together with genetic investigations. Here, we aimed to assess the correlation between the different alleles of VDR gene polymorphisms and renal cell cancer and breast cancer risks separately through a systematic review of the present literature. In contrast, this analysis has revealed that some VDR gene polymorphisms, such as: Bsm1, poly(A), Taq1, Apa1, are to some extent associated with breast cancer risk. Other polymorphisms were found to be significantly associated with renal cell cancer. Namely, they were Fok1, Bsm1, Taq1 and Apa1, which encode proteins participating mainly in proliferation, apoptosis and cell cycle regulation. However, data concerning renal cancer are not sufficient to firmly establish the VDR gene polymorphism association.

Abstract A39: Gene-environment interactions between SNPs in the renin-angiotensin-aldosterone system and hypertension, obesity, and blood pressure-related dietary exposures regarding renal cell cancer risk

Abstract Background: Hypertension and obesity may increase renal cell cancer (RCC) risk, but the underlying mechanism is not well understood. Given that sodium, potassium and fluid intake influence blood pressure (BP), genetic variants in the renin-angiotensin-aldosterone system (RAAS) may constitute to RCC development, as RAAS regulates BP and sodium balance. Methods: The Netherlands Cohort Study on diet and cancer with case-cohort design includes 120,852 participants aged 55-69 years. At baseline, diet and lifestyle factors were assessed using questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the iPLEX Gold system and MassARRAY software (Sequenom, Hamburg). After 20.3 years of follow-up, 13 candidate single nucleotide polymorphisms (SNPs) in seven RAAS genes known to be involved in BP regulation or sodium balance were available for Cox proportional hazards analyses for 3,583 subcohort members and 503 cases. Results: Two SNPs, AGTR1_rs1492078 (AA vs. GG) and AGTR1_rs5186 (CC vs. AA), were associated with RCC risk in the total population [hazard ratio (95% confidence interval): 0.70 (0.49-1.00) and 1.49 (1.08-2.05), respectively] and in participants with hypertension. AGT_rs3889728 (AA + AG vs. GG) showed a lower RCC risk in participants with hypertension and a higher RCC risk in participants without hypertension (P-interaction = 0.039). Associations between sodium intake and RCC risk differed among genotypes of RAAS SNPs, but tests for these and other SNP-environment interactions were not significant. Conclusion: SNPs in AGTR1 and the interplay between AGT_rs889728 and hypertension may influence RCC susceptibility. SNP-environment interactions with obesity, potassium intake and fluid intake were not significant. For sodium intake we can neither conclude nor exclude that such interactions may contribute to RCC risk. Citation Format: Ivette AG Deckers, Piet A. van den Brandt, Manon van Engeland, Roger Godschalk, Leo J. Schouten. Gene-environment interactions between SNPs in the renin-angiotensin-aldosterone system and hypertension, obesity, and blood pressure-related dietary exposures regarding renal cell cancer risk. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A39.

A Genetic Variant in pre-miR-27a Is Associated with a Reduced Renal Cell Cancer Risk in a Chinese Population

BackgroundMicroRNAs (miRNAs) are a class of small non-coding RNAs to regulate cell differentiation, proliferation, development, and apoptosis. The single nucleotide polymorphism (SNP) rs895819 is located at the terminal loop of pre-miR-27a. Here, we aimed to investigate whether SNP rs895819 was associated with the development of renal cell cancer (RCC) in a Chinese population.MethodsIn this case-control study, we recruited 594 RCC patients and 600 cancer-free controls with frequency matched by age and sex. We genotyped this polymorphism using the TaqMan assay and assessed the effect of this polymorphism on RCC survival. Logistic regression model was used to assess the genetic effects on the development of RCC and interactions between rs895819 polymorphism and risk factors.ResultsCompared with AA homozygote, individuals carrying AG/GG genotypes had a statistically significant reduced susceptibility to RCC (adjusted OR = 0.71, 95% CI = 0.56–0.90). Furthermore, AG/GG genotypes were associated with reduced RCC susceptibility in localized clinical stage (adjusted OR = 0.71, 95% CI = 0.55–0.91), and similar effects were observed in well differentiated and poorly differentiated RCC (adjusted OR = 0.71, 95% CI = 0.55–0.93 for well differentiated, adjusted OR = 0.51, 95% CI = 0.28–0.93 for poorly differentiated). We also observed that rs895819 had multiplicative interactions with age and hypertension. However, the polymorphism did not influence the survival of RCC.ConclusionOur results suggest that the pre-miR-27a rs895819 polymorphism can predict RCC risk in a Chinese population. Larger population-based prospective studies should be used to validate our findings.

Renal cell cancer among African Americans: an epidemiologic review

Incidence rates for renal cell cancer, which accounts for 85% of kidney cancers, have been rising more rapidly among blacks than whites, almost entirely accounted for by an excess of localized disease. This excess dates back to the 1970s, despite less access among blacks to imaging procedures in the past. In contrast, mortality rates for this cancer have been virtually identical among blacks and whites since the early 1990s, despite the fact that nephrectomy rates, regardless of stage, are lower among blacks than among whites. These observations suggest that renal cell cancer may be a less aggressive tumor in blacks. We have reviewed the epidemiology of renal cell cancer, with emphasis on factors which may potentially play a role in the observed differences in incidence and mortality patterns of renal cell cancer among blacks and whites. To date, the factors most consistently, albeit modestly, associated with increased renal cell cancer risk in epidemiologic studies among whites - obesity, hypertension, cigarette smoking - likely account for less than half of these cancers, and there is virtually no epidemiologic evidence in the literature pertaining to their association with renal cell cancer among blacks. There is a long overdue need for detailed etiologic cohort and case-control studies of renal cell cancer among blacks, as they now represent the population at highest risk in the United States. In particular, investigation of the influence on renal cell cancer development of hypertension and chronic kidney disease, both of which occur substantially more frequently among blacks, is warranted, as well as investigations into the biology and natural history of this cancer among blacks.

Fibronectin 1 mRNA expression correlates with advanced disease in renal cancer

BackgroundFibronectin 1 (FN1) is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to elucidate the role of FN1 in development of renal cell cancer (RCC) and to determine a prognostic relevance for optimal clinical management.Methods212 renal tissue samples (109 RCC, 86 corresponding tissues from adjacent normal renal tissue and 17 oncocytomas) were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Detection of FN1 mRNA expression was performed using quantitative real time PCR, three endogenous controls, renal proximal tubular epithelial cells (RPTEC) as biological control and the ΔΔCt method for calculation of relative quantities.ResultsMean tissue specific FN1 mRNA expression was found to be increased approximately seven fold comparing RCC and corresponding kidney control tissues (p < 0.001; ANOVA). Furthermore, tissue specific mean FN1 expression was increased approx. 11 fold in clear cell compared to papillary RCC (p = 9×10-5; Wilcoxon rank sum test). Patients with advanced disease had higher FN1 expression when compared to organ-confined disease (p < 0.001; Wilcoxon rank sum test). Applying subgroup analysis we found a significantly higher FN1 mRNA expression between organ-confined and advanced disease in the papillary and not in the clear cell RCC group (p = 0.02 vs. p = 0.2; Wilcoxon rank sum test). There was an increased expression in RCC compared to oncocytoma (p = 0.016; ANOVA).ConclusionsTo our knowledge, this is the first study to show that FN1 mRNA expression is higher in RCC compared to normal renal tissue. FN1 mRNA expression might serve as a marker for RCC aggressiveness, indicating early systemic progression particularly for patients with papillary RCC.

The tumor suppressor gene FBXW7 is disrupted by a constitutional t(3;4)(q21;q31) in a patient with renal cell cancer

FBXW7 (alias CDC4) is a p53-dependent tumor suppressor gene that exhibits mutations or deletions in a variety of human tumors. Mutation or deletion of the FBXW7 gene has been associated with an increase in chromosomal instability and cell cycle progression. In addition, the FBXW7 protein has been found to act as a component of the ubiquitin proteasome system and to degrade several oncogenic proteins that function in cellular growth regulatory pathways. By using a rapid breakpoint cloning procedure in a case of renal cell cancer (RCC), we found that the FBXW7 gene was disrupted by a constitutional t(3;4)(q21;q31). Subsequent analysis of the tumor tissue revealed the presence of several anomalies, including loss of the derivative chromosome 3. Upon screening of a cohort of 29 independent primary RCCs, we identified one novel pathogenic mutation, suggesting that the FBXW7 gene may also play a role in the development of sporadic RCCs. In addition, we screened a cohort of 48 unrelated familial RCC cases with unknown etiology. Except for several known or benign sequence variants such as single nucleotide polymorphisms (SNPs), no additional pathogenic variants were found. Previous mouse models have suggested that the FBXW7 gene may play a role in the predisposition to tumor development. Here we report that disruption of this gene may predispose to the development of human RCC.

Association Between Local Atherosclerosis and Renal Cell Carcinomas

Objective: Atherosclerosis induce changes in reactive oxygen species and oxidative stress by hypoxia leading to oxidative DNA damage and therefore it could be expected that the cancer risk in patients with atherosclerotic diseases is increased. Materials and Methods: The present study therefore aimed to morphometrically compare atherosclerotic changes (e.g., intima-to-media ratio [IMR]) in renal cell cancer (n = 514) and tumor-negative renal specimens (n = 70). Results: Renal cell cancer specimens, in contrast to tumor-negative renal specimens, had more advanced atherosclerotic lesions, which moreover in immediately peritumorous (near-field) arteries were more strongly developed than in somewhat more distant (far-field) arteries. IMR > 1 was significantly associated with renal cell carcinoma and the odds ratio of having renal cell cancer was significantly higher for patients with an IMR > 1. Conclusion: Local atherosclerosis was more pronounced in tumor-positive than in tumor-negative renal specimens with significant association between IMR > 1 and renal cancer. This finding encourages the hypothesis of atherosclerosis causing oxidative stress as a potential risk factor for the development of renal cell cancer.