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The purpose of the present study was to investigate whether genetic variants that influence angiogenesis and sorafenib pharmacokinetics are associated with clinical outcomes and toxic effects in advanced renal cell carcinoma patients treated with this drug. One hundred patients with advanced renal cell carcinoma were enrolled. Forty-two polymorphisms in 15 genes were selected for genotyping and analyzed for associations with progression-free survival, overall survival, and toxic effects. We found that rs1570360 in VEGF and rs2239702 in VEGFR2 were significantly associated with progression-free. Specifically, patients carrying the variant genotypes (AG + AA) of these two polymorphisms both had an unfavorable progression-free. In addition, compared with those with the rs2239702 GG genotype, patients with the AG + AA genotype suffered an unfavorable OS. We found that the VEGF rs2010963 CG + GG genotypes had a significantly increased risk of hand-foot syndrome, and the ABCB1 rs1045642 CT + TT genotypes had an increased risk of high blood pressure. Our results suggest that polymorphisms in VEGF and VEGFR2 are associated with sorafenib clinical outcomes, and polymorphisms in VEGF and ABCB1 are associated with sorafenib-related toxicities. Larger studies are warranted to validate our findings.

Objective: To assess the technique and short-term outcomes of laparoscopic partial nephrectomy (LPN) with precise segmental renal artery clamping for clinical T1b (cT1b) tumors and to analyze the possible factors affecting the glomerular filtration rate (GFR) reduction., Materials and Methods: This retrospective study investigated the outcomes of 72 patients with cT1b tumors who received LPN from June 2008 to May 2014. Based on three-dimensional dynamic renal vascular models built before surgery, target arteries were precisely clamped and tumors were removed under regional parenchymal ischemia. Perioperative and follow-up outcomes were analyzed., Results: All the LPN procedures were effectively performed using the novel technique, without converting to main renal artery clamping or open surgery. The mean operative time was 86 min, with a mean warm ischemic time of 25 min. The median estimated blood loss was 200 mL (range: 80-800). The postoperative mean GFR was 64% of the preoperative baseline, and the total complication rate was 19.4%. In multivariable analyses, the two independent factors affecting postoperative GFR were the RENAL nephrometry score (RNS) and number of intraoperative clamped segmental arteries. The median follow-up was 24 months (range: 6-72). The overall, recurrence-free, and cancer-specific survival rates were 100%, 95.8%, and 100%, respectively., Conclusions: For patients with cT1b tumor, LPN with precise segmental renal artery clamping is safe and feasible for removing tumors and preserving the blood supply and normal renal parenchyma. Short-term oncologic and functional outcomes were satisfactory. Postoperative GFR was related to the preoperative RNS and number of intraoperative clamped segmental arteries.

Background: Radical nephrectomy with inferior vena cava (IVC) thrombectomy is the preferred treatment for renal cell carcinoma (RCC) with IVC thrombus. However, IVC thrombectomy using a laparoscopic approach has not been reported for high-level thrombi., Objective: To describe the surgical technique for laparoscopic IVC thrombectomy in patients with different thrombus levels and to assess its safety and feasibility., Design, Setting, and Participants: Retrospective review of medical records for 11 patients with right-side RCC, including six patients with level II IVC thrombus and five patients with level IV thrombus., Surgical Procedure: Laparoscopic thrombectomy for level II thrombus was performed after clamping the infrarenal IVC, left renal vein, and infrahepatic IVC. Laparoscopic thrombectomy and thoracoscope-assisted open atriotomy for level IV thrombus were performed after establishing cardiopulmonary bypass and clamping the infrarenal IVC, left renal vein, and hepatoduodenal ligament., Measurements: The intraoperative variables, postoperative complications, and surgical outcomes were assessed., Results and Limitations: The median operative time was 210min. The median IVC clamping time for patients with level II and level IV thrombus was 16.5 and 31min, respectively. The median estimated blood loss was 510ml, and no major intraoperative or postoperative complications occurred. One patient with level IV thrombus died of brain metastasis 6 mo after the operation, and the remaining ten patients had no local recurrence or distant metastasis during a median follow-up period of 31 mo., Conclusions: Laparoscopic IVC thrombectomy for level II thrombus and well-selected level IV thrombus may be a safe and technically feasible alternative to open surgery., Patient Summary: We studied the treatment of patients with an inferior vena cava thrombus at different levels using a laparoscopic approach. This technique was safe and feasible in well-selected patients., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The RhoA/ROCK pathway and Caveolin-1 (Cav-1) participate in the process of tumorigenesis in numerous types of cancer. Up-regulation of RhoA/ROCK and Cav-1 expression is considered to be associated with the development and progression of clear cell renal cell carcinoma (ccRCC). We investigated the association between genetic variations of RhoA/ROCK and Cav-1 and the risk of ccRCC in the Chinese population., Methods: Between May 2004 and March 2014, a total of 1,248 clear cell renal cell carcinoma cases and 1,440 cancer-free controls were enrolled in this hospital-based case-control study. Nine SNPs in RhoA/ROCK and Cav-1 were genotyped using the TaqMan assay., Result: We found two SNPs (Cav-1 rs1049334 and ROCK1 rs35996865) were significantly associated with the increasing risk of ccRCC (P = 0.002 and P < 0.001 respectively). The analysis of combined risk alleles revealed that patients with 2-4 risk alleles showed a more remarkable growth of ccRCC risk than the patients with 0-1 risk alleles(OR = 1.66, 95%CI = 1.31-2.11, P < 0.001). Younger subjects (P = 0.001, OR = 1.83, 95%CI = 1.30-2.57), higher weight subjects (P = 0.001, OR = 1.76, 95%CI = 1.25-2.47), female subjects (P = 0.007, OR = 1.75, 95% CI = 1.17-2.62), nonsmokers (P < 0.001, OR = 1.67, 95%CI = 1.26-2.23), drinkers (P = 0.025, OR = 1.75, 95% CI = 1.07-2.85), subjects with hypertension (P = 0.025, OR = 1.75, 95% CI = 1.07-2.85) and diabetes (P = 0.026, OR = 4.31, 95% CI = 1.19-15.62) showed a stronger association between the combined risk alleles and the risk of ccRCC by using the stratification analysis. Furthermore, we observed higher Cav-1 mRNA levels in the presence of the rs1049334 A allele in normal renal tissues., Conclusion: Our results indicate that the two SNPs (Cav-1 rs1049334 and ROCK1 rs35996865) and genotypes with a combination of 2-4 risk alleles were associated with the risk of ccRCC. The functional SNP rs1049334 may affect the risk of ccRCC by altering the expression of Cav-1 and the relevance between the risk effects and the functional impact of this polymorphism needs further validation.

Aberrant microRNAs (miRNAs) are reported to contribute to the pathogenesis of most human malignancies. The miRNA, miR-134, has been found to be downregulated in renal cell carcinoma (RCC), but its function in the disease is unknown. The aims of this study were to detect the expression of miR-134 in human RCC samples and explore its function in RCC cell lines. Real-time qualitative polymerase chain reaction (qPCR) was used to quantify miR-134 in human RCC samples. Assays for cell cycle, viability, migration, and invasion were performed to assess the phenotypic changes in RCC cells. A luciferase reporter assay was carried out to confirm whether KRAS (Kirsten rat sarcoma viral oncogene homolog) is a direct target of miR-134. Western blot was used to identify the potential signaling pathways that had an impact on RCC cell growth and alterations of markers for epithelial-mesenchymal transition (EMT), which affected metastasis by miR-134. miR-134 was found to be downregulated in RCC samples (p<0.05), while overexpression of miR-134 suppressed proliferation (p<0.05) by triggering G1/G0 cell cycle arrest (p<0.05). Forced expression of miR-134 could also inhibit migration (p<0.05) and invasion (p<0.05) by blocking EMT in RCC cell lines. KRAS was identified as a target of miR-134, and miR-134 may act as a tumor suppressor through the KRAS-related MAPK/ERK pathway other than PI3K/AKT signaling. Thus, miR-134 may function as a tumor suppressor in cell proliferation and EMT by targeting KRAS in RCC cells.

Angiogenesis is fundamentally important to the pathogenesis of clear cell renal cell carcinoma (ccRCC). We investigated the association between variations of genes related to angiogenesis and the risk of ccRCC. In a case-control study of 859 ccRCC patients and 1004 cancer-free subjects, we genotyped 24 potentially functional single nucleotide polymorphisms (SNPs) in seven angiogenesis-related genes (HIF1A, EPAS1, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) using the TaqMan or Snapshot method. Unconditional logistic regression, adjusted for potential confounding factors, was used to assess the risk associations. The functionality of selected SNPs was assessed by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and luciferase reporter gene assays. We found two SNPs (VEGFA rs2010963 and VEGFR3 rs448012) that were significantly associated with increased risk of ccRCC, after adjusting for multiple comparisons [rs2010963 CC/GC cf. GG: false discovery rate (FDR) = 0.048, odds ratio (OR) = 1.36, 95% confidence interval (95% CI) = 1.12-1.66; rs448012 CC/GC cf. GG: FDR = 0.048, OR = 1.38, 95% CI =1.13-1.69]. Real-time quantitative PCR revealed that the variant genotypes of rs2010963, but not rs448012, were associated with increased gene expression in normal tissues of ccRCC patients (CC/GC cf. GG: P = 0.036). The luciferase reporter assay showed that the rs2010963 C allele significantly increased luciferase activity over that of the rs2010963 G allele. Our results indicate that VEGFA rs2010963 and VEGFR3 rs448012 are associated with risk of ccRCC. Furthermore, rs2010963 is a functional SNP that may affect ccRCC susceptibility by modulating endogenous VEGFA expression., (© The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Raf-1 kinase inhibitor protein (RKIP) plays a critical role in tumor development by regulating cell functions such as invasion, apoptosis and differentiation. Down-regulation of RKIP expression has been implicated in the development and progression of renal cell carcinoma (RCC). Herein, we hypothesized that genetic polymorphisms in RKIP might be associated with susceptibility and progression of RCC., Methods: A total of 5 tagging single-nucleotide polymorphisms (tSNPs) in RKIP were selected and genotyped by SNapShot method in a case-control study of 859 RCC patients and 1004 controls. The logistic regression was used to evaluate the genetic association with occurrence and progression of RCC. The functionality of the important SNP was preliminary examined by qRT-PCR., Result: We found that the rs17512051 in the promoter region of RKIP was significantly associated with decreased clear cell RCC (ccRCC) risk (TA/AA vs. TT: P = 0.039, OR = 0.78, 95%CI = 0.62-0.99). Another SNP (rs1051470) in the 3'UTR region of RKIP was marginally associated with increased ccRCC risk (TT vs. CC+CT: OR = 1.45, 95%CI = 1.01-2.09). In the stratified analysis, the protective effect of rs17512051 was more predominant in the subgroups of male, non-smokers, non-drinkers as well as subjects without history of diabetes. Furthermore, we observed higher RKIP mRNA levels in the presence of the rs17512051A allele in normal renal tissues., Conclusion: Our results suggest that the potentially functional RKIP rs17512051 polymorphism may affect ccRCC susceptibility through altering the endogenous RKIP expression level. Risk effects and the functional impact of this polymorphism need further validation.

The incidence of renal cell carcinoma (RCC) has been steadily rising each year. There are currently few recognized biomarkers for the diagnosis and prognosis of RCC. We investigated semenogelin I (Sg I) expression and its clinical significance in patients with RCC. The expression levels of Sg I and its protein were measured by qPCR and Western blotting, respectively. Immunohistochemistry was used to investigate the protein expression of Sg I in RCC and normal renal tissue from 53 patients. The Kaplan-Meier method and log-rank test were used to evaluate the data. By qRCR (p < 0.01) and Western blot, the level of Sg I expression in benign tissues was higher than that in RCC tissues. Expression of Sg I was observed in 30 (57 %) RCC cases, which was significantly lower than that observed in benign renal tissues from the same patients [Sg I positive in 53 (100 %) cases (p < 0.0001)] by immunohistochemistry. There was an inverse relation between Sg I expression and clinical stage (pT1-2 vs pT3-4, p < 0.0001). Patients with Sg I-negative tumor had a significantly higher risk of recurrence (Kaplan-Meier and log-rank tests, p < 0.0001). There was low Sg I expression in RCC. Sg I expression has potential value in predicting cancer progression and prognosis. These findings support the use of Sg I as a novel biomarker for RCC.

MicroRNAs (miRNAs) are a class of short non-coding, single-stranded RNAs, which perform posttranscriptional regulatory functions as tumor suppressors or oncogenes. Single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) genes are currently being identified for contributing to cancer risk, prognosis and survival. We investigated whether genetic variations of miRNAs were associated with the risk and prognosis of renal cell carcinoma (RCC). We genotyped four common miRNA SNPs (i.e. miR-146a rs2910164, miR-149 rs2292832, miR-196a2 rs11614913 and miR-499 rs3746444) to assess their associations with RCC risk in a two-stage case-control study (355 cases and 362 controls in discovery set, meanwhile 647 cases and 660 controls in validation set), as well as RCC survival in 311 patients. We found that the miR-196a2 SNP rs11614913 was associated with RCC susceptibility in recessive model [CC versus TT/TC, adjusted odds ratio = 0.65, 95% confidence interval (CI) = 0.52-0.83] and with survival of RCC in dominant model (TC/CC versus TT, adjusted hazard ratio = 0.40, 95% CI = 0.18-0.89). Meanwhile, the rs11614913 CC genotype was associated with the significantly decreased expression of miR-196a-5p in 26 renal cancer tissues (P = 0.018). Moreover, luciferase reporter assays revealed the potential effect of rs11614913 SNP on the binding of miR-196a-3p to its targets. These results suggested that the miR-196a2 rs11614913 may contribute to the genetic susceptibility and prognosis for RCC, which may act as a biomarker for RCC occurrence and prognosis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Recent large-scale transcriptome analyses have found large numbers of transcripts, including that of long non-coding RNAs (lncRNAs), which are aberrant in various diseases, especially cancers. However, it is not clear whether lncRNAs are involved specifically in renal cell carcinoma (RCC). We investigated the expression patterns of lncRNAs in five RCC tumor samples (T) relative to those of matched adjacent non-tumor tissues (N) via microarray., Methods: A microarray with 33,045 lncRNA probes and 30,215 mRNA probes was used to identify deregulated lncRNAs in five RCC patients. Furthermore, we confirmed the relative expression levels of AK096725 and ENST00000453068 in 70 paired samples by quantitative reverse transcription polymerase chain reaction (qRT-PCR)., Results: The lncRNA microarray revealed 27,279 lncRNAs in RCC samples, of which 480 were significantly upregulated (P<0.05; T/N>1.5) and 417 were significantly downregulated (P<0.05; N/T>1.5) compared with the matched non-tumor samples. In addition, 19,995 mRNAs were detected, of which 458 were significantly upregulated (P<0.05; T/N>1.5) and 413 were significantly downregulated (P<0.05; N/T>1.5). The expression level changes of AK096725 (P = 0.043) and ENST00000453068 (P<0.001) in 70 paired samples were in accord with the microarray data., Conclusions: The study uncovered expression patterns of lncRNAs in 5 RCC patients, as well as a number of aberrant lncRNAs and mRNAs in tumor samples compared with the non-tumor tissues. The revelation of an association between AK096725 expression and RCC is especially noteworthy. These findings may help to find new biomarkers in RCC.

Background: We aimed to evaluate the feasibility and clinical significance of using a modified liver-mobilization technique to treat renal cell carcinoma (RCC) combined with intrahepatic inferior vena cava (IVC) thrombosis., Methods: A total of 11 level III thrombus patients underwent radical nephrectomy with resection of the tumor thrombus from intrahepatic IVC. A father clamp was used in combination with hepatic portal blocking to control the IVC., Results: The intraoperative mortality and postoperative complications were reduced in 11 cases of RCC with intrahepatic IVC thrombosis. The mean blood loss was 800 mL, and mean patient hospital stay was 13 days. Follow-up was conducted for one to four months, with only two cases of recurrence recorded., Conclusions: The proposed modified liver-mobilization technique could safely and effectively treat RCC and reduce intrahepatic IVC thrombosis.

Members of the miR-34 family have been shown to be transcriptional targets of the tumour suppressor gene P53. Aberration expression of miR-34 impairs p53-mediated cell cycle arrest and apoptosis. A single nucleotide polymorphism T > C (rs4938723) located within the CpG island in the promoter region of pri-miR-34b/c may affect its expression and has been suggested to influence cancer risk. In this study, we genotyped rs4938723 using the TaqMan method to explore the relationship between this polymorphism and the risk of renal cell cancer (RCC) in a case-control study of 710 RCC patients and 760 control subjects. We found that individuals carrying the CC genotype had a significantly increased RCC risk compared with those with TT or TT/TC genotypes [odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.06-2.21 for CC vs. TT and OR = 1.48, 95% CI = 1.05-2.10 for CC vs. TT/TC). Furthermore, the increased risk was more evident in the subgroups of older subjects (OR = 1.80, 95% CI = 1.08-3.01), males (OR = 1.64, 95% CI = 1.08-2.51), smokers (OR = 2.07, 95% CI = 1.16-3.69) and drinkers (OR = 1.94, 95% CI = 1.01-3.73), although no interaction between rs4938723 and these characteristics was observed. Twenty-seven normal tissues adjacent to tumour were used to evaluate the association between the expression level of miR-34b/c and the polymorphism, which revealed higher expression levels of miR-34b/c in normal renal tissues with TT+TC genotypes than in those with CC genotypes (P < 0.01). Furthermore, a luciferase gene assay in 293-T cells showed that the luciferase activities with rs4938723 T allele are higher than that with C allele (P < 0.05). These results suggest that the miR-34b/c rs4938723 C allele may increase susceptibility to RCC by decreasing the activity of pri-miR-34b/c promoter.

Background: One-carbon metabolism is the basement of nucleotide synthesis and the methylation of DNA linked to cancer risk. Variations in one-carbon metabolism genes are reported to affect the risk of many cancers, including renal cancer, but little knowledge about this mechanism is known in Chinese population., Methods: Each subject donated 5 mL venous blood after signing the agreement. The study was approved by the Institutional Review Board of the Nanjing Medical University, Nanjing, China. 18 SNPs in six one-carbon metabolism-related genes (CBS, MTHFR, MTR, MTRR, SHMT1, and TYMS) were genotyped in 859 clear cell renal cell carcinoma (ccRCC) patients and 1005 cancer-free controls by the Snapshot., Results: Strong associations with ccRCC risk were observed for rs706209 (P = 0.006) in CBS and rs9332 (P = 0.027) in MTRR. Compared with those carrying none variant allele, individuals carrying one or more variant alleles in these two genes had a statistically significantly decreased risk of ccRCC [P = 0.001, adjusted odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.06-0.90]. In addition, patients carrying one or more variant alleles were more likely to develop localized stage disease (P = 0.002, adjusted OR = 1.37, 95%CI = 1.11-1.69) and well-differentiated ccRCC (P<0.001, adjusted OR = 1.42, 95%CI = 0.87-1.68). In the subgroup analysis, individuals carrying none variant allele in older group (P = 0.007, adjusted OR = 0.67, 95%CI = 0.49-0.91), male group (P = 0.007, adjusted OR = 0.71, 95%CI = 0.55-0.92), never smoking group (P = 0.002, adjusted OR = 0.68, 95%CI = 0.53-0.88) and never drinking group (P<0.001, adjusted OR = 0.68, 95%CI = 0.53-0.88) had an increased ccRCC risk., Conclusions: Our results suggest that the polymorphisms of the one-carbon metabolism-related genes are associated with ccRCC risk in Chinese population. Future population-based prospective studies are required to confirm the results.

Background: To summarize the diagnosis and treatment of cystic renal cell carcinoma (CRCC)., Methods: A retrospective study was conducted on 13 patients with CRCC at our center from August 2004 to April 2012. The pathologic features, clinical manifestation, imaging characteristics, treatment, and prognosis of CRCC were summarized according to available literature., Results: Of the 13 patients, 11 were diagnosed with CRCC by preoperative B ultrasonography and computed tomography (CT) scan. The remaining two cases were initially misdiagnosed with simple renal cysts. Open radical nephrectomy was performed on two of the 13 cases, laparoscopic radical nephrectomy on seven cases, and open partial nephrectomy on four cases. All diagnoses of CRCC were confirmed by pathological examination. After the operation, all patients had an uneventful recovery. During the follow-up (range, 6-60 months), the serum creatinine concentrations and GFR of the partially removed kidneys remained stable within the normal range. No tumor recurrence or metastasis occurred., Conclusions: By combining imaging examinations (B ultrasonography and CT scan) with intraoperative pathological examination, most cases of CRCC can be diagnosed and treated promptly and accurately. Nephrectomy is the first-line therapy. Nephron-sparing surgery should be preferred for CRCC. After a successful operation, the prognosis of CRCC is good.

Objective: To investigate the expression pattern of Sprouty2 (Spry2) and its clinicopathologic significance among patients with renal cell carcinoma (RCC) and to detect its role in proliferation and invasion of RCC in vitro., Materials and Methods: The expression profile of Spry2 in RCC and matched adjacent noncancerous tissues were detected by immunohistochemistry and Western blot analysis. The expression of Spry2 was depleted by stably transfecting with small, interfering ribonucleic acid and the effects of Spry2 were assessed using the cell proliferation and transwell assay., Results: We found Spry2 protein expressed at lower levels and modestly downregulated in cancerous RCC tissues compared with adjacent normal tissue (P <.001). We also measured the expression level of Spry2 in 103 archived RCC tissues by immunohistochemical staining and found its correlation with clinicopathologic findings such as tumor size (P = .002), pathologic TNM stage (P <.001), tumor grade (P <.001), lymph node metastasis (P = .001), distant metastasis (P <.001), and poor survival (P = .001). In addition, small interfering ribonucleic acid-induced depletion of Spry2 expression promoted proliferation and invasion in RCC cell lines., Conclusion: Collectively, our results have demonstrated for the first time, to our knowledge, that Spry2 might offer an attractive new target for prognostic and therapeutic intervention in RCC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Clamping the segmental renal artery instead of the main renal artery during nephron-sparing surgery is a promising technique to decrease warm ischemia injury. Understanding vasculature characteristics and adopting an appropriate hilar approach to segmental arteries are essential to the technique., Objective: To study the role of the vasculature model and to standardize the renal hilar approach in segmental renal artery dissection during laparoscopic partial nephrectomy (LPN)., Design, Setting, and Participants: A retrospective analysis of a consecutive series of 82 patients who underwent LPN with a precise clamping technique from December 2009 to June 2011 with a mean follow-up of 20 mo., Surgical Procedure: Three-dimensional dynamic renal vascular models were established based on dual-source computed tomographic angiography. Clamping number, clamping position, and a different hilar approach accessing target segmental arteries were determined preoperatively. Target arteries were dissected and clamped based on the model. Tumor excision and renorrhaphy were performed under regional parenchymal ischemia., Outcome Measurements and Statistical Analysis: Renal vascular characteristics and surgical outcomes were analyzed. The outcomes among different surgical approaches were compared using one-way analysis of variance test or Fisher exact test., Results and Limitations: All surgeries were performed successfully without converting to main renal artery clamping or radical nephrectomy. The median operative time was 90 min, and the mean clamping time was 24 min. The median estimated blood loss (EBL) was 200 ml, and six patients received blood transfusions. Five patients had hematuria without any intervention. One patient had a postoperative hemorrhage and received selective embolization intervention. Statistical analysis showed that appropriate surgical approaches chosen from the models led to comparable operative times, EBL, and complication rates. The limitation of the study lies on its retrospective feature., Conclusions: A renal vasculature model provides effective orientation for a precise clamping technique. A standardized hilar approach based on the model optimizes the surgical procedure and leads to satisfactory surgical outcomes., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Activated nuclear factor-ĸB is associated with the pathogenesis of numerous malignancies, including renal cell carcinoma (RCC). This study aimed to clarify the influence of a common insertion/deletion polymorphism (-94 ins/del ATTG, rs28362491) in the NFKB1 promoter on RCC susceptibility., Methods: We genotyped the NFKB1 -94 ins/del ATTG promoter polymorphism by the TaqMan method and assessed the association with RCC risk, clinicopathological parameters in a case-control study of 1,027 cases and 1,094 controls., Results: The genotype frequencies were significantly different between RCC cases and controls (p = 0.046). Compared with individuals carrying the ins/del + del/del genotypes, those with the ins/ins genotype had an increased RCC risk [p = 0.036, adjusted odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.02-1.48], particularly in the subgroup of younger age (p = 0.005, adjusted OR = 1.42, 95% CI = 1.11-1.83) and never smokers (p = 0.013, adjusted OR = 1.34, 95% CI = 1.07-1.69). Furthermore, the polymorphism was significantly associated with the risk of developing localized stage RCC (p = 0.020, OR = 1.26, 95% CI = 1.04-1.53)., Conclusions: The functional NFKB1 promoter polymorphism is associated with an increased risk of RCC., (© 2013 S. Karger AG, Basel.)

The DNA repair gene Ku70 plays a key role in the DNA double strand break (DSB) repair system. Defects in DSB repair capacity can lead to genomic instability. We hypothesized that the Ku70 C-1310G polymorphism (rs2267437) was associated with risk of renal cell carcinoma (RCC). We genotyped the Ku70 C-1310G polymorphism in a case-control study of 620 patients and 623 controls in a Chinese population and assessed the effects of C-1310G polymorphism on RCC susceptibility and survival. We then examined the functionality of this polymorphism. Compared with the Ku70-1310CC genotype, the CG and CG/GG genotypes had a significantly increased risk of RCC [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.16-1.87 for CG and OR = 1.47, 95% CI = 1.16-1.86 for CG/GG]. However, the C-1310G polymorphism did not influence the survival of RCC. The in vivo experiments with normal renal tissues revealed statistically significantly lower Ku70 mRNA expression in samples with CG/GG genotypes relative to those with the CC genotype (P < 0.05). In vitro luciferase assays in various cell lines showed lower luciferase activity for the -1310G allele than for the -1310C allele. These results suggest that the Ku70 C-1310G polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC in Chinese populations. Larger studies are warranted to validate our findings., (Copyright © 2012 Wiley Periodicals, Inc.)

The DNA repair gene Ku70 plays a key role in the DNA double-strand breaks (DSBs) repair system. Defects in DSBs repair capacity can lead to genomic instability. We hypothesized that the Ku70 A-31G polymorphism (rs132770) was associated with the risk of renal cell carcinoma (RCC). In a hospital-based case-control study of 620 RCC patients and 623 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism Ku70 A-31G (rs132770). Thirty-eight normal renal tissue samples with different genotypes were tested to estimate the Ku70 mRNA expression by real-time quantitative reverse transcription. Compared with the GG genotype, the GA and GA/AA genotypes had a significantly decreased risk of RCC [adjusted odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.44-0.87 for GA, and OR = 0.62, 95% CI = 0.45-0.86 for GA/AA]. The in vivo experiments with normal renal tissues revealed that a statistically significantly higher Ku70 mRNA expression was identified in samples with GA/AA genotypes compared with those with GG genotypes (p = 0.001). These results suggested that the Ku70 A-31G polymorphism is involved in the etiology of RCC and, thus, may be a marker for genetic susceptibility to RCC in the Chinese populations.

A recent genome-wide association study of renal cell carcinoma (RCC) in European population has identified genetic variants in the regions of 2p21 (rs7579899), 11q13.3 (rs7105934) and 12q24.31 (rs4765623) conferred susceptibility to RCC. In our study, we assessed whether these polymorphisms are also associated with RCC risk in a Chinese population. We genotyped these polymorphisms using TaqMan method and assessed their associations with RCC risk in a case-control study of 710 patients with histologically confirmed RCC and 760 cancer-free controls. Normal renal tissues adjacent to tumors were used to evaluate the functional consequences of these polymorphisms. We found that rs7105934 was significantly associated with reduced RCC risk [adjusted odds ratio (OR) = 0.67, 95% confidence intervals (CIs) = 0.47-0.95, GA+AA versus GG], particularly among subgroups of normal-weight individuals (OR = 0.51, 95%CI = 0.29-0.88), never-smokers (OR = 0.53, 95%CI = 0.33-0.85) and non-drinkers (OR = 0.57, 95%CI = 0.370.87). Furthermore, the rs7105934 GA genotype was associated with lower levels of CCND1 mRNA compared with GG genotype, although this association was only marginally significant (P = 0.055). No significant association between rs7579899 or rs7105934 and RCC risk was observed. Our results suggest that rs7105934 on 11q13.3 may confer susceptibility to RCC in our population. Large population-based prospective and functional studies are required to validate the associations between these loci and RCC risk.

Background: Survivin is an inhibitor of apoptosis protein and is involved in the occurrence and progression of human malignancies. Recently, a functional polymorphism (-31G>C, rs9904341) in the promoter of survivin has been shown to influence its expression and confer susceptibility to different types of cancer. The present study was aimed to investigate whether the polymorphism also influences susceptibility and progression of renal cell cancer (RCC) in a Chinese population., Methods: We genotyped this polymorphism using the TaqMan assay in a case-control study comprised of 710 RCC patients and 760 controls. The logistic regression was used to assess the genetic association with occurrence and progression of RCC., Results: Compared with the genotypes containing G allele (GG and GC), we found a statistically significant increased occurrence of RCC associated with the CC genotype [P = 0.006, adjusted odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.08-1.76]. The polymorphism was associated with risk of developing advanced stage (OR = 2.02, 95%CI = 1.34-3.07) and moderately differentiated (OR = 1.75; 95%CI = 1.20-2.54) RCC. Furthermore, the patients carrying the CC genotype had a significantly greater prevalence of high clinical stage disease (P(trend) = 0.003). Similar results were also observed when we restricted the analysis to clear cell RCC, a major histological type of RCC., Conclusions: Our results suggest that the functional -31G>C polymorphism in the promoter of survivin may influence the susceptibility and progression of RCC in the Chinese population. Large population-based prospective studies are required to validate our findings.

Background: The mTOR signaling pathway plays a crucial role in the carcinogenesis of renal cell cancer (RCC). We sought to investigate the influence of genetic variations in the mTOR pathway-related genes on the risk of RCC., Methods: We genotyped 8 potentially functional polymorphisms in AKT1, AKT2, PTEN and MTOR genes using the TaqMan method in a case-control study of 710 RCC patients and 760 cancer-free subjects. Unconditional logistic regression, adjusted for potential confounding factors, was used to assess the risk associations. We then examined the functionality of the important polymorphisms., Results: Of the 8 polymorphisms, after adjusting for multiple comparisons, we found a significant association between one variant (rs2295080) in the promoter of MTOR and reduced RCC risk (P = 0.005, OR = 0.74, 95%CI = 0.59-0.91, TG/GG vs. TT). Another variant (rs701848) in the 3'UTR region of PTEN was associated with increased RCC risk (P = 0.014, OR = 1.45, 95%CI = 1.08-1.96, CC vs. TT); however, the association was not significant after adjusting for multiple comparisons. Furthermore, we observed lower MTOR mRNA levels in the presence of the rs2295080G allele in normal renal tissues. The luciferase reporter assay showed that the rs2295080G allele significantly decreased luciferase activity. No other significant association between the selected polymorphisms and RCC risk was observed., Conclusions: Our results suggest that the functional MTOR promoter rs2295080 variant affects RCC susceptibility by modulating the endogenous MTOR expression level. The risk effects and the functional impact of the MTOR rs2295080 variant need further validation.

Background: MicroRNAs (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., Methods: In 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., Results: Compared 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., Conclusion: Our 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.

Apurinic/apyrimidinic endonuclease 1 (APE1) is a DNA repair protein, which plays important roles in the base excision repair (BER) pathway. Genetic variations of APE1 have been shown to influence an individual's susceptibility to carcinogenesis. We hypothesized the genetic polymorphisms of APE1 are associated with the risk of renal cell carcinoma (RCC). In a case-control study of 612 RCC patients and 632 age and sex matched healthy controls, we genotyped two APE1 functional polymorphisms (-656 T>G, rs1760944 and 1349 T>G, rs1130409) and assessed their associations with risk of RCC. We found that, compared with 1349 TT/TG genotypes, the variant genotype 1349 GG had a significantly increased RCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.10-1.95], particularly among subgroups of BMI > 23 kg/m(2) (OR = 1.54, 95% CI = 1.06-2.22), male (OR = 1.70, 95% CI = 1.17-2.46), never smokers (OR = 1.56, 95% CI = 1.11-2.21), light smokers (OR = 2.01, 95%CI = 1.02-3.95), and drinkers (OR = 2.00, 95% CI = 1.13-3.54). Furthermore, the polymorphism was significantly associated with risk of developing localized stage RCC. No altered RCC risk was associated with the -656 T>G polymorphism, but we found individuals who were homozygous for both risk alleles of the two SNPs had a 2.17-fold increased risk for RCC, compared to individuals with 0 risk alleles. Our results suggest that polymorphisms of APE1 may confer susceptibility to RCC., (Copyright © 2011 Wiley Periodicals, Inc.)

Oxidative DNA damage caused by reactive oxygen species plays an important role in cancer development. Human 8-oxoguanine DNA glycosylase (hOGG1) is involved in base excision repair of 8-oxoguanine from damaged DNA. We hypothesized that variants in the hOGG1 gene are associated with risk of renal cell carcinoma (RCC). In a hospital-based case-control study of 572 RCC patients and 575 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism Ser326Cys (rs1052133) and assessed its associations with risk of RCC in a Chinese population. We found that individuals with the Cys allele were associated with an increased risk of RCC (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.02-1.90), compared with those with the Ser/Ser genotype, particularly among subgroups of body mass index >24 kg/m(2) (OR = 1.75, 95% CI = 1.12-2.73) and non-smokers (OR = 1.60, 95% CI = 1.07-2.38). Further, the polymorphism was associated with risk of developing localized stage and well-differentiated RCC. Our results suggested that the polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC.

Objectives: Interleukin-16 (IL-16) plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. A T-to-C polymorphism at the -295 position in the promoter region of the IL-16 gene has been described. This variation might lead to altered IL-16 expression, and might modulate an individual's susceptibility to cancer. The objective of the present study was to determine if IL-16 polymorphism is associated with risk of renal cell carcinoma (RCC)., Methods: A case-control study including 335 RCC cases and 340 cancer-free controls was carried out. All subjects were genetically unrelated ethnic Han Chinese recruited from a single institution between July 2006 and July 2009. The IL-16 -295 T>C polymorphism was determined by using the polymerase chain reaction-restriction fragment length polymorphism method. Serum samples were available for 70 RCC cases and 96 controls to detect IL-16 concentration., Results: Compared with the IL-16 -295 TT genotype, the CC genotype had a significantly decreased RCC risk (adjusted odds ratio [OR] = 0.34, 95% confidence interval [CI] = 0.18-0.66). Furthermore, a significant decreased risk of RCC was found in the combined variant genotypes CT + CC compared with the TT genotype (adjusted OR = 0.68, 95% CI = 0.50-0.93). In addition, the serum IL-16 levels in RCC patients were significantly lower than those in controls (P < 0.001). Furthermore, patients carrying CC genotype or CT genotype had higher serum IL-16 levels than TT carriers., Conclusion: IL-16 -295 T>C polymorphism is significantly associated with a higher risk of developing RCC in Chinese population.

The epidermal growth factor (EGF) gene encodes a growth factor that binds to the EGF receptor (EGFR), which is involved in activating pathways that promote cellular proliferation, survival, migration and differentiation, and lack of control is characteristic of malignant development. Previous studies showed that serum EGF levels may influence the risk of cancer. In this study, we genotyped the EGF G61A polymorphism (rs4444903) and measured serum EGF levels using an enzyme immunoassay in a hospital-based case-control study of 345 patients with diagnosed renal cell carcinoma (RCC) and 346 cancer-free controls in a Chinese population. Compared with the EGF 61GG genotype, the AA genotype had a significantly increased RCC risk (odds ratio=1.80, 95% confidence interval=1.04-3.12). Besides, the mean serum EGF levels in RCC patients (858.94+/-391.54 pg ml(-1)) were significantly lower than those in controls (1281.52+/-568.42 pg ml(-1), P<0.001). In addition, individuals carrying AA genotype had lower serum EGF levels than GA or GG carriers. These results suggested that the EGF G61A polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC in Chinese populations. Larger studies are warranted to validate our findings.