Renal cell carcinoma management: A step to nano-chemoprevention.

Renal cell carcinoma (RCC) is one of the most common kidney cancers, responsible for nearly 90 % of all renal malignancies. Despite the availability of many treatment strategies, RCC still remains to be an incurable disease due to its resistivity towards conventional therapies. Nanotechnology is an emerging field of science that offers newer possibilities in therapeutics including cancer medicine, specifically by targeted delivery of anticancer drugs. Several phytochemicals are known for their anti-cancer properties and have been regarded as chemopreventive agents. However, the hydrophobic nature of many phytochemicals decreases its bioavailability and distribution, thus showing limited therapeutic effect. Application of nanotechnology to enhance chemoprevention is an effective strategy to increase the bioavailability of phytochemicals and thereby its therapeutic efficacy. The present review focuses on the utility of nanotechnology in RCC treatment and chemopreventive agents of RCC. We have also visualized the future prospects of nanomolecules in the prevention and cure of RCC.

Immunization with short peptide particles reveals a functional CD8+ T-cell neoepitope in a murine renal carcinoma model.

BACKGROUND: Induction of CD8+ T cells that recognize immunogenic, mutated protein fragments in the context of major histocompatibility class I (MHC-I) is a pressing challenge for cancer vaccine development. METHODS: Using the commonly used murine renal adenocarcinoma RENCA cancer model, MHC-I restricted neoepitopes are predicted following next-generation sequencing. Candidate neoepitopes are screened in mice using a potent cancer vaccine adjuvant system that converts short peptides into immunogenic nanoparticles. An identified functional neoepitope vaccine is then tested in various therapeutic experimental tumor settings. RESULTS: Conversion of 20 short MHC-I restricted neoepitope candidates into immunogenic nanoparticles results in antitumor responses with multivalent vaccination. Only a single neoepitope candidate, Nesprin-2 L4492R (Nes2LR), induced functional responses but still did so when included within 20-plex or 60-plex particles. Immunization with the short Nes2LR neoepitope with the immunogenic particle-inducing vaccine adjuvant prevented tumor growth at doses multiple orders of magnitude less than with other vaccine adjuvants, which were ineffective. Nes2LR vaccination inhibited or eradicated disease in subcutaneous, experimental lung metastasis and orthotopic tumor models, synergizing with immune checkpoint blockade. CONCLUSION: These findings establish the feasibility of using short, MHC-I-restricted neoepitopes for straightforward immunization with multivalent or validated neoepitopes to induce cytotoxic CD8+ T cells. Furthermore, the Nes2LR neoepitope could be useful for preclinical studies involving renal cell carcinoma immunotherapy.

Dietary and circulating vitamin D and risk of renal cell carcinoma: a meta-analysis of observational studies

ABSTRACT Objective: This meta-analysis is the first to evaluate the associations of circulating and dietary intake of vitamin D with risk of risk of renal cell carcinoma (RCC). Our findings showed that higher circulating vitamin D level and dietary vitamin D intake were associated with a reduced risk of RCC. The possible explanation might be attributed to the anti-inflammatory effect, inhibiting cell proliferation, inducing cell differentiation and apoptosis. Materials and Methods: We searched the MEDLINE, EMBASE, and Scopus databases from their inception points through December 2018 for observational studies. The pooled relative risks (RRs) with corresponding 95% CIs were calculated using random-effects or fixed-effects models. The Newcastle-Ottawa scale was employed to assess the quality of the included studies. Results: A total of 9 publications were included in this meta-analysis. An overall analysis of the highest versus lowest intake levels revealed that circulating vitamin D level was protectively associated with risk of RCC 0.76 (95% CI: 0.64-0.89, P=0.001), with no evidence of heterogeneity (I2=38.8%, P=0.162). In addition, dietary vitamin D intake was associated with a reduced risk of RCC (RR: 0.86; 95% CI: 75-0.99, P=0.030). Statistical heterogeneity was not identified (I2=28.8%, P=0.199). Subgroup analyses results showed the gender differences, and the associations were significant in results with women participants (RR: 0.70; 95% CI: 0.55-0.88) and case-control studies (RR: 0.80, 95% CI: 0.67-0.95). Conclusion: Higher circulating vitamin D level and higher dietary vitamin D intake both might be associated with a reduced risk of RCC. Further high-quality randomized controlled trials are required in the future to confirm our results.

Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10.

The microRNA let-7d has been reported to be a tumor suppressor in renal cell carcinoma (RCC). Tumor-associated macrophages (TAM) are M2-polarized macrophages that can enhance tumor growth and angiogenesis in many human cancers. However, the role of let-7d in TAM-associated RCC progression remains elusive. First, we observed a strongly inverse correlation between let-7d expression and microvessel density in RCC tissues. Furthermore, the proliferation, migration, and tube formation of HUVECs were significantly inhibited by conditioned medium from a coculture system of the phorbol myristate acetate pretreated human THP-1 macrophages and let-7d-overexpressing RCC cells. Moreover, the proportion of M2 macrophages was significantly lower in the group that was cocultured with let-7d-overexpressing RCC cells. Subcutaneous xenografts formed by the injection of let-7d-overexpressing RCC cells together with THP-1 cells resulted in a significant decrease in the M2 macrophage ratio and microvessel density compared with those formed by the injection of control RCC cells with THP-1 cells. In silico and experimental analysis revealed interleukin-10 (IL-10) and IL-13 as let-7d target genes. Importantly, the addition of IL-10 and IL-13 counteracted the inhibitory effects of the conditioned medium from the coculture system with let-7d-overexpressing RCC cells in vitro. Additionally, overexpression of IL-10 and IL-13 reversed the effects of let-7d on macrophage M2 polarization and tumor angiogenesis in vivo. Finally, the expression of IL-10 and IL-13 were inversely correlated with the expression of let-7d in RCC clinical specimens. These results suggest that let-7d may inhibit intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-10 and IL-13.

Dietary and circulating vitamin D and risk of renal cell carcinoma: a meta-analysis of observational studies.

OBJECTIVE: This meta-analysis is the first to evaluate the associations of circulating and dietary intake of vitamin D with risk of risk of renal cell carcinoma (RCC). Our findings showed that higher circulating vitamin D level and dietary vitamin D intake were associated with a reduced risk of RCC. The possible explanation might be attributed to the anti-inflammatory effect, inhibiting cell proliferation, inducing cell differentiation and apoptosis. MATERIALS AND METHODS: We searched the MEDLINE, EMBASE, and Scopus databases from their inception points through December 2018 for observational studies. The pooled relative risks (RRs) with corresponding 95% CIs were calculated using random-effects or fixed-effects models. The Newcastle-Ottawa scale was employed to assess the quality of the included studies. RESULTS: A total of 9 publications were included in this meta-analysis. An overall analysis of the highest versus lowest intake levels revealed that circulating vitamin D level was protectively associated with risk of RCC 0.76 (95% CI: 0.64-0.89, P=0.001), with no evidence of heterogeneity (I2=38.8%, P=0.162). In addition, dietary vitamin D intake was associated with a reduced risk of RCC (RR: 0.86; 95% CI: 75-0.99, P=0.030). Statistical heterogeneity was not identified (I2=28.8%, P=0.199). Subgroup analyses results showed the gender differences, and the associations were significant in results with women participants (RR: 0.70; 95% CI: 0.55-0.88) and case-control studies (RR: 0.80, 95% CI: 0.67-0.95). CONCLUSION: Higher circulating vitamin D level and higher dietary vitamin D intake both might be associated with a reduced risk of RCC. Further high-quality randomized controlled trials are required in the future to confirm our results.

The anti-inflammatory protein MCPIP1 inhibits the development of ccRCC by maintaining high levels of tumour suppressors.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. It is highly vascularized and largely resistant to traditional chemo- and radiotherapy. Decreases in tumour suppressors and low levels of the anti-inflammatory Monocyte Chemoattractant Protein-Induced Protein 1 (MCPIP1) play important roles in the development and progression of ccRCC. MCPIP1, also called Regnase-1, possesses endonuclease activity and degrades the mRNA of proinflammatory cytokines such as IL-6, IL-1ß, IL-12 and IL-2. We previously showed that the level of MCPIP1 decreases with ccRCC progression. In this study, we explored the role of MCPIP1 in regulating the levels of tumour suppressors. We found low levels of the suppressors PTEN, RECK and TIMP3 and high levels of MMPs in patients with ccRCC who had already been shown to have low MCPIP1 expression. We demonstrated that MCPIP1 regulates the expression levels of PTEN, RECK and TIMP3 in ccRCC cell lines as well as in vivo models of ccRCC. MCPIP1 overexpression increased the expression of tumour suppressors. Moreover, we observed that the RNase activity of MCPIP1 is responsible for the modulation of apoptosis and activation of prometastatic signalling pathways. Furthermore, we found a negative correlation between high levels of IL6, a direct target of MCPIP1 RNase activity, and TIMP3 in patients, indicating that MCPIP1 and TIMP3 might collectively cause the high levels of IL6 in ccRCC patients. Taken together, our results show the importance of MCPIP1 in regulating the level of tumour suppressors and, consequently, in ccRCC development and progression.

PTPN3 Inhibits the Growth and Metastasis of Clear Cell Renal Cell Carcinoma via Inhibition of PI3K/AKT Signaling.

The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is still to be explored. The significant downregulation of protein tyrosine phosphatase nonreceptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. IHC analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 was an independently favorable prognostic factor for progression-free survival (P = 0.0166) and overall survival (P = 0.0343) of patients. The ccRCC cell lines SN12C, 1932, ACHN, and Caki-1 were used to evaluate, both in vitro and in vivo, the biological roles of PTPN3. We observed that overexpression of PTPN3 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. In contrast, the knocking down of PTPN3 elicited opposite effects. Overexpressing PTPN3 inhibited xenograft tumor growth and lung metastasis displayed by the in vivo mice models. PTPN3 inhibited tumor cell motility by suppressing the phosphorylation of AKT, and subsequently inactivating the PI3K/AKT signaling pathway of renal cell carcinoma cells. Furthermore, the inhibition of phospho-AKTThr308 and phospho-AKTSer473 reversed PTPN3-induced silencing in tumor cell migration. Our work revealed that the overexpression of PTPN3 could suppress kidney cancer progression by negatively regulating the AKT signaling pathway, and served as a favorable prognostic factor in patients with ccRCC. Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC. IMPLICATIONS: PTPN3 is an independent favorable prognostic factor for patients with ccRCC and could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.

Statin use and the risk of renal cell carcinoma: national cohort study.

Statins are a therapeutic drug with reducing plasma cholesterol levels and have been linked with potential antitumor effects. However, epidemiological studies on statin use and renal cell carcinoma (RCC) risk have been inconsistent. This cohort study aimed to examine this association in an Asian population. We identified patients who filled initial prescriptions for statins in the inpatient and ambulatory care order files from Taiwan's National Health Insurance Research Database between January 1, 1998 and December 31, 2005 as the statin users cohort (n=14,067). The comparison cohort comprised of patients who had not taken any statin in the previous years prior to January 1, 1998 or had used statins for less than 28 cumulative defined daily doses between January 1, 1998 and December 31, 2005 (n=56 268). The outcome of interest was pathologically verified RCC occurred between January 1, 1999 and December 31, 2013. The Fine-Gray competing risk model was fitted to estimate HRs accompanying 95% CI. Patients with the use of statins had a significantly lower risk of RCC as compared with the non-users cohort, yielding an adjusted HR of 0.64 (95% CI, 0.38 to 0.87). Moreover, we found a significant inverse association between cumulative statin use and the risk of RCC. Further, the inverse association between statin use and risk of RCC was evident in both sexes. This population-based cohort study provides longitudinal evidence that the use of statins was associated with a reduced risk of RCC.

Systematic review of modifiable risk factors for kidney cancer.

To perform a systematic review of modifiable risk factors associated with the incidence of renal cell cancer (RCC). A systematic search of the literature was conducted using PubMed, Cochrane, and Web of Science databases from January 1996 until August 2017. We also extracted articles from the reference lists of identified studies and reviews. We targeted modifiable risk factors for RCC to include exercise, smoking, alcohol, diet, obesity, hypertension, and diabetes. We utilized predefined inclusion criteria and the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. We identified a total of 464 relevant articles and excluded 209 via title and 130 after abstract review. We thoroughly reviewed a total of 125 manuscripts. Seven supplementary tables describe (a) case controls and (b) prospective cohort studies. We summarize the tables in figures to visualize the overall impact of these studies association (beneficial, harmful, or null) with RCC. Total physical activity if beneficial (10/12 studies), smoking is harmful (13/14 studies), alcohol was protective (i.e., beneficial, 13/16 studies), diet was indeterminate (13 beneficial, 13 harmful, and 9 nulls), obesity and hypertension were overwhelmingly harmful (36/36 studies and 17/18, respectively), and diabetes was detrimental (23/27 studies). Modifiable risk factors play an essential role in the development of RCC, and we should develop targeted RCC prevention strategies in at-risk individuals.

MiR-31-5p acts as a tumor suppressor in renal cell carcinoma by targeting cyclin-dependent kinase 1 (CDK1).

BACKGROUND: Renal cell carcinoma (RCC) accounts for more than 90% of cancers in the kidney. RCC is often asymptomatic, as a result people with RCC generally have advanced disease by the time it is discovered and has a poor prognosis compared to other cancers. Therefore, it is necessary to explore its pathogenesis and identify some reliable prognostic biomarker of RCC. miRNAs are emerging as important players in the development and progression of RCC. miR-31-5p has been reported to act as a tumor suppressor in hepatocellular carcinoma (HCC). The aim of this study is to determine the detailed molecular mechanism of miR-31-5p in the progression of RCC and to investigate its potential clinical value. METHODS: In this study, RT-qPCR, EdU assay, CCK-8 assay, wound scratch assay, transwell assay, flow cytometry assay and cell cycle assay were performed to detect miR-31-5p expression and its functions in RCC. Moreover, 42 formalin-fixed paraffin-embedded (FFPE) RCC samples were used to analyze the relationship between miR-31-5p expression and patients' overall survival. Finally, luciferase reporter assay, RT-qPCR assay and western blot were used to explore the association between miR-31-5p and its potential targets. RESULTS: miR-31-5p was significantly down-regulated in RCC tissues and RCC cell lines compared with paired adjacent normal tissues and normal cell lines. miR-31-5p downregulation was associated with poor prognosis in RCC patients. Overexpression of miR-31-5p inhibited RCC cell proliferation, migration and invasion and cell cycle. Conversely, down-regulation of miR-31-5p promoted cell proliferation, migration and invasion. Furthermore, cyclin-dependent kinasec1 (CDK1), a key player in cell cycle regulation, was identified as a functional target of miR-31-5p. CONCLUSIONS: Our results suggest that miR-31-5p serves as a tumor suppressor in RCC and is expected to be a molecular biomarker for poor prognosis of RCC.

Modifiable risk factors to reduce renal cell carcinoma incidence: Insight from the PLCO trial.

INTRODUCTION: Identify modifiable factors contributing to renal cell carcinoma in the PCLO to target disease prevention and reduce health care costs. METHODS: The prostate, lung, colorectal, and ovarian database were queried for the primary outcome of kidney cancer. Demographics were investigated, specifically focusing on modifiable risk factors. Statistical analysis includes the Student t-test for continuous variables, chi-squared or Fisher's exact tests for dichotomous and categorical variables for bivariate analysis. The Cox proportional hazards model was used in a multivariate time-to-event analysis. RESULTS: We investigate existing data relating specifically to renal cancer. After missing data were excluded, we analyzed 149,683 subjects enrolled in the prostate, lung, colorectal, and ovarian trial and noted 0.5% (n = 748) subjects developed renal cancer. Age, male gender, body mass index, diabetes, and hypertension were all significant associated with renal cancer in bivariate analysis (P<0.05). Men have a significant increased risk of kidney cancer over women (hazard ratio [HR] = 1.85; 95% CI: 1.58-2.16; P<0.0001). Nonmodifiable risk factors that are associated with kidney cancer include age (HR = 1.05; 95% CI: 1.01; 1.05, P = 0.001). Modifiable risk factors include obesity measured by body mass index (HR = 1.05; 95% CI: 1.02-1.07; P<0.0001), hypertension (HR = 1.32; 95% CI: 1.13-1.54; P = 0.0004), and smoking in pack-years (HR = 1.04; 95% CI: 1.02-1.07; P = 0.0002). CONCLUSIONS: Obesity, hypertension, and smoking are the 3 modifiable risk factors that could aggressively be targeted to reduce renal cell carcinoma.

Racial Disparities and Preventive Measures to Renal Cell Carcinoma.

Kidney cancer ranks among the top 10 cancers in the United States. Although it affects both male and female populations, it is more common in males. The prevalence rate of renal cell carcinoma (RCC), which represents about 85% of kidney cancers, has been increasing gradually in many developed countries. Family history has been considered as one of the most relevant risk factors for kidney cancer, although most forms of an inherited predisposition for RCC only account for less than four percent. Lifestyle and other factors such as occupational exposure, high blood pressure, poor diet, and heavy cigarette smoking are highly associated with its incidence and mortality rates. In the United States, White populations have the lowest prevalence of RCC compared to other ethnic groups, while Black Americans suffer disproportionally from the adverse effects of RCC. Hence, this review article aims at identifying the major risk factors associated with RCC and highlighting the new therapeutic approaches for its control/prevention. To achieve this specific aim, articles in peer-reviewed journals with a primary focus on risk factors related to kidney cancer and on strategies to reduce RCC were identified. The review was systematically conducted by searching the databases of MEDLINE, PUBMED Central, and Google Scholar libraries for original articles. From the search, we found that the incidence and mortality rates of RCC are strongly associated with four main risk factors, including family history (genetics), lifestyle (poor diet, cigarette smoking, excess alcohol drinking), environment (community where people live), and occupation (place where people work). In addition, unequal access to improvement in RCC cancer treatment, limited access to screening and diagnosis, and limited access to kidney transplant significantly contribute to the difference observed in survival rate between African Americans and Caucasians. There is also scientific evidence suggesting that some physicians contribute to racial disparities when performing kidney transplant among minority populations. New therapeutic measures should be taken to prevent or reduce RCC, especially among African Americans, the most vulnerable population group.

Hormonal manipulation with finasteride or oral contraception does not influence incidence of renal cell carcinoma.

Androgens have been suspected to be involved in the initiation of renal cell carcinoma because of a two-fold increased risk in men compared with women. To investigate the role of self-reported finasteride or oral contraceptive use in the Prostate, Lung, Colorectal, and Ovarian (PCLO) to determine whether the androgen receptor reduces renal cancer development. We query the PCLO trial for predictor variables from the baseline questionnaire and follow-up questionnaires enquiring medication use, specifically the use of 5-α reductase inhibitors (dutasteride or finasteride) and oral contraceptive therapy. The primary outcome of this study was the incidence of renal cancer. Statistical analysis included Student's t-test for continuous variables, χ, or Fisher's exact tests for dichotomous or categorical variables, and multivariable analysis using Cox proportional hazards models. Eight percent (n=6117/73 694) of men in the PCLO trial reported the use of finasteride. 52 (10.6%) of the 492 men diagnosed with renal cancer had self-reported exposure to finasteride and this was not significant in univariable analysis (52/6169; 0.84% vs. 440/66 454; 0.67%, P=0.12) or multivariable main effects analysis (hazard ratio: 1.12; 95% confidence interval: 0.83-1.5; P=0.47). Approximately 54% of women (n=40 997/75 989) in the PCLO trial reported the use of oral contraceptives by questionnaire. 136 (52.1%) of the 261 women diagnosed with renal cancer had self-reported exposure to oral contraceptive therapy and this was not significant in univariable analysis (136/40 997; 0.33% vs. 125/34 992; 0.36%, P=0.36) or in multivariable main effects analysis (hazard ratio: 1.03; 95% confidence interval: 0.97-1.1; P=0.30). Self-reported use of finasteride or oral contraceptives is not associated with a reduced incidence of renal cancer.

Prevention of kidney cancer incidence and recurrence: lifestyle, medication and nutrition.

PURPOSE OF REVIEW: The incidence of kidney cancer rises globally with the highest rates in developed countries. This demonstrates the impact of advanced diagnostic imaging but also rising prevalence of modifiable risk factors such as smoking, obesity and hypertension. A literature search was performed with focus on recent studies on risk factors related to lifestyle, medication and nutrition. Further we searched for the effect of cancer prevention strategies. RECENT FINDINGS: Overall, we included 76 studies of the past 5 years. Based on current evidence smoking tobacco, obesity and hypertension remain established risk factors for kidney cancer. Certain analgesics and consumption of processed meat have been linked to increase development of renal cell carcinoma, although data are limited. Fruits, fiber-rich vegetables, coffee and physical activity may have a protective effect against kidney cancer but causal conclusions are not yet supported. Significantly, there is an increasing evidence of inverse association between moderate alcohol consumption. SUMMARY: Overall evidence confirms an effective way to prevent the risk of kidney cancer is maintaining a healthy weight and avoid smoking. State policies should further ensure strategies to raise public awareness and support to adopt healthy lifestyles.

Vasohibin-1 inhibits angiogenesis and suppresses tumor growth in renal cell carcinoma.

Vasohibin-1 (VASH1) has recently been isolated as a novel inhibitor of angiogenesis. Several studies have demonstrated that VASH1 plays important roles in tumor angiogenesis but the role of this angiogenic inhibitor in renal cell carcinoma (RCC) has not been elucidated. We previously reported that VASH1 expression is reduced and is associated with clinicopathological features in RCC. In the present study, we investigated the biological effects of VASH1 in RCC by evaluating the effects of VASH1 on cell proliferation, cell cycle distribution, cell apoptosis and cell invasion in human umbilical vein endothelial cells (HUVECs) and 786-0 cells, and evaluating the effect of VASH1 on the growth of 786-0 cells in nude mice. A pReceiver-M61-VASH1 was transfected into HUVECs and 786-0 cells, and the expression level of VASH1 protein was examined by western blotting. Cell proliferation was detected by MTT assay, and cell cycle and apoptosis of HUVECs and 786-0 cells were analyzed by flow cytometry. The invasive ability of 786-0 cells was tested by Transwell assay. Finally, nude mouse models were established to evaluate the therapeutic effect of VASH1. The pReceiver-M61-VASH1 effectively induced the expression of VASH1 in HUVECs and 786-0 cells. VASH1 overexpression effectively inhibited cell proliferation, arrested the cell cycle in the G0/G1 phase and promoted cell apoptosis of HUVECs and 786-0 cells. VASH1 overexpression effectively inhibited the subcutaneous growth of 786-0 tumors in vivo. Therefore, VASH1 is a potential molecular-targeted therapy for patients with RCC.

Consumption of fruits and vegetables and risk of renal cell carcinoma: a meta-analysis of observational studies.

BACKGROUND: There have been inconsistent results about the association between consumption of fruits and vegetables and renal cell carcinoma (RCC) risk. We conducted a meta-analysis of the published observational studies to explore this association. RESULTS: Nineteen observational studies (4 cohort, 1 pooled and 14 case-control studies), involving 10,215 subjects with RCC were part of this meta-analysis. The SRR for the highest vs. the lowest intake of vegetables was 0.73 (95% CI: 0.63-0.85; Pheterogeneity = 0.004, I2 = 53.5%), whereas for fruits it was 0.86 (95% CI: 0.75-0.98; Pheterogeneity = 0.012, I2 = 47.4%). Linear dose-response analysis also showed similar results, e.g., for per 1 serving/day increment of vegetables, the SRR was 0.90 (95% CI: 0.84-0.96) and for fruits it was 0.97 (95% CI: 0.93-1.01). Nonlinear association was only observed for vegetables (Pnonlinearity = 0.001), but not for fruits (Pnonlinearity = 0.221). MATERIALS AND METHODS: Eligible studies up to August 31, 2016 were identified and retrieved by searching MEDLINE and EMBASE databases along with manual review of the reference list from the retrieved studies. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale (NOS). Random-effects model was used to calculate summary relative risk (SRR) and corresponding 95% confidence interval (CI). CONCLUSIONS: This meta-analysis indicated a protective effect of consumption of vegetables and fruits on RCC risk. Further studies are warranted with prospective designs that use validated questionnaires and control for important confounders.

Alcohol and Dietary Folate Intake and Promoter CpG Island Methylation in Clear-Cell Renal Cell Cancer.

We investigated whether alcohol and dietary folate intakes were associated with promoter methylation in clear-cell renal cell carcinoma (ccRCC). The Netherlands Cohort Study with a case-cohort design included 120,852 subjects aged 55-69 yr in 1986. Diet was measured with a food-frequency questionnaire. After 20.3 yr of follow-up, paraffin-embedded tumor blocks were collected. Methylation-specific polymerase chain reaction (MSP) was used to analyze promoter methylation of 11 genes. ccRCC cases were classified into low (0-19% of the genes), intermediate (20-39%), and high (40%+) methylation. Multivariable Cox regression analyses were conducted, stratified according to methylation, including 3980 subcohort members and 297 ccRCC cases. Increasing alcohol intake was associated with decreased ccRCC risk, but was not statistically significant; multivariable adjusted hazard ratio (HR) for ≥30 g alcohol/day versus 0 g/day was 0.78 [95% confidence interval (CI): 0.48-1.24], and P-value for trend was 0.46. In strata according to methylation index, no significant heterogeneity was observed. Dietary folate intake was not associated with ccRCC risk. There was no significant heterogeneity between strata according to methylation index. There was no effect modification of alcohol and dietary folate intake on ccRCC risk, nor in strata according to methylation index. Our findings do not support the hypothesis that alcohol and dietary folate intakes are involved in ccRCC.

Long-term Use of Statins and Risk of Renal Cell Carcinoma: A Population-based Case-Control Study.

BACKGROUND: Use of statins has been suggested to protect against renal cell carcinoma (RCC); however, studies have typically been underpowered, and the results are conflicting. OBJECTIVE: To determine whether the use of statins is associated with a reduced risk of RCC using high-quality registry data. DESIGN, SETTING, AND PARTICIPANTS: We conducted a nationwide case-control study based on all histologically verified cases of RCC in Denmark between 2002 and 2012 (n=4606) matched 1:10 to cancer-free controls. Data on drug use, comorbidity, and educational level were obtained from Danish nationwide prescription, patient, and demographic registries. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) and 95% confidence intervals (CIs) for RCC associated with long-term use (≥5 yr) of statins were estimated using conditional logistic regression, adjusting for potential confounders. RESULTS AND LIMITATIONS: The adjusted OR for RCC associated with long-term use of statins was 1.06 (95% CI, 0.91-1.23). Analyses stratified by duration of statin use, type of statin, and patient characteristics all yielded ORs close to unity, except for a slightly increased OR for RCC associated with long-term statin use among women (OR: 1.25; 95% CI, 0.96-1.62). The main limitation of our study was lack of information on lifestyle factors, notably obesity, which may have biased the risk estimates upward. CONCLUSIONS: Our study does not support an important chemopreventive effect of long-term statin use against RCC. The marginally increased and statistically insignificant risk estimates can readily be interpreted as a null finding, considering the lack of control for obesity and other lifestyle risk factors. PATIENT SUMMARY: Previous studies have shown that the use of cholesterol-lowering drugs (statins) may protect against renal cancer. In a large study including all Danish renal cancers during an 11-yr period, we found no evidence of such an effect.