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We performed a series of integrative analyses including transcriptome-wide association studies (TWASs) and proteome-wide association studies (PWASs) of renal cell carcinoma (RCC) to nominate and prioritize molecular targets for laboratory investigation. On the basis of a genome-wide association study (GWAS) of 29,020 affected individuals and 835,670 control individuals and prediction models trained in transcriptomic reference models, our TWAS across four kidney transcriptomes (GTEx kidney cortex, kidney tubules, TCGA-KIRC [The Cancer Genome Atlas kidney renal clear-cell carcinoma], and TCGA-KIRP [TCGA kidney renal papillary cell carcinoma]) identified 38 gene associations (false-discovery rate <5%) in at least two of four transcriptomic panels and identified 12 genes that were independent of GWAS susceptibility regions. Analyses combining TWAS associations across 48 tissues from GTEx identified associations that were replicable in tumor transcriptomes for 23 additional genes. Analyses by the two major histologic types (clear-cell RCC and papillary RCC) revealed subtype-specific associations, although at least three gene associations were common to both subtypes. PWAS identified 13 associated proteins, all mapping to GWAS-significant loci. TWAS-identified genes were enriched for active enhancer or promoter regions in RCC tumors and hypoxia-inducible factor binding sites in relevant cell lines. Using gene expression correlation, common cancers (breast and prostate) and RCC risk factors (e.g., hypertension and BMI) display genetic contributions shared with RCC. Our work identifies potential molecular targets for RCC susceptibility for downstream functional investigation., Competing Interests: Declaration of interests K.S. receives research support from Gilead, GSK, Novo Nordisk, Bayer, Regeneron, Calico, and Novartis. K.S. is on the advisory board of Jnana Therapeutics and has received consulting fees from Pfizer and Jnana. Declaration of interests for the Renal Cancer Genetics Consortium, which contributed toward acquisition of the individual-level data, can be referred to as a part of Purdue et al.(10) The other named authors in the manuscript have no competing interests to declare. It is to be noted that the individual-level data contributed by The Renal Cancer Genetics Consortium is now publicly available, and the current analyses were conducted with summary-level data only., (Published by Elsevier Inc.)

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden 1 . In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence 2 . Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics., (© 2024. The Author(s).)

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent organic pollutants detectable in the serum of most U.S. adults. We previously reported a positive association between serum perfluorooctanoate (PFOA) concentrations and risk of renal cell carcinoma (RCC) within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, comprising predominantly White individuals enrolled in 1993-2001. To extend our investigations to a larger and more racially and ethnically diverse population, we conducted a nested case-control study of serum PFAS concentrations and RCC within the Multiethnic Cohort Study. We measured pre-diagnostic serum concentrations of nine PFAS among 428 RCC cases and 428 individually matched controls. We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for risk of RCC in relation to each PFAS using conditional logistic regression, adjusting for RCC risk factors and other PFAS. PFOA was not associated with RCC risk overall [doubling in serum concentration, OR continuous  = 0.89 (95 %CI = 0.67, 1.18)]. However, we observed suggestive positive associations among White participants [2.12 (0.87, 5.18)] and among participants who had blood drawn before 2002 [1.49 (0.77, 2.87)]. Furthermore, higher perfluorononanoate (PFNA) concentration was associated with increased risk of RCC overall [fourth vs. first quartile, OR = 1.84 (0.97, 3.50), P trend  = 0.04; OR continuous  = 1.29 (0.97, 1.71)], with the strongest association observed among African American participants [OR continuous  = 3.69 (1.33, 10.25)], followed by Native Hawaiian [2.24 (0.70, 7.19)] and White [1.98 (0.92, 4.25)] participants. Most other PFAS were not associated with RCC. While PFOA was not associated with RCC risk overall in this racially and ethnically diverse population, the positive associations observed among White participants and those with sera collected before 2002 are consistent with previous PLCO findings. Our study also provided new evidence of a positive association between PFNA and RCC risk that was strongest in African American participants. These findings highlight the need for additional epidemiologic research investigating PFAS exposures and RCC in large racially and ethnically diverse populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Large-scale human genetic data 1-3 have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL) 4-6 . VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization 6,7 . We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8 ). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants., (© 2022. The Author(s).)

Purpose: There is increasing evidence that coffee consumption is related to reduced risks for some cancers, but the evidence for renal cancer is inconclusive. Therefore, we conducted a meta-analysis to summarize the cohort evidence of this relationship., Methods: A literature search was performed in PubMed and Embase through February 2021. Meta-analyses using a random effects model were conducted for reported relative risk estimates (RRs) relating coffee intake and renal cancer incidence or mortality. We also performed a two-stage random effects exposure-response meta-analysis. Between-study heterogeneity was assessed., Results: In a meta-analysis of the ten identified cohort studies, we found a summary RR of 0.88 [95% confidence interval (CI) 0.78-0.99] relating the highest vs. the lowest category of coffee intake and renal cancer, with no significant between-study heterogeneity observed (I 2  = 35%, p = 0.13). This inverse association remained among studies of incident cancers (RR 0.85, 95% CI 0.76-0.96) and studies adjusting for smoking and body mass index (RR 0.87, 95% CI 0.77-0.99)., Conclusions: Our findings from this meta-analysis of the published cohort evidence are suggestive of an inverse association between coffee consumption and renal cancer risk., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer., Significance: We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease. This article is highlighted in the In This Issue feature, p. 2945., (©2021 American Association for Cancer Research.)

Background: Coffee consumption has been associated with a reduced risk of some cancers, but the evidence for renal cell carcinoma (RCC) is inconclusive. We investigated the relationship between coffee and RCC within a large cohort., Methods: Coffee intake was assessed at baseline in the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Among 420 118 participants eligible for analysis, 2674 incident cases were identified. We fitted Cox-regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee consumption vs non-drinkers., Results: We observed HRs of 0.94 (95% CI 0.81, 1.09), 0.94 (0.81, 1.09), 0.80 (0.70, 0.92) and 0.77 (0.66, 0.90) for usual coffee intake of <1, 1, 2-3 and ≥4 cups/day, respectively (Ptrend = 0.00003). This relationship was observed among never-smokers (≥4 cups/day: HR 0.62, 95% CI 0.46, 0.83; Ptrend = 0.000003) but not ever-smokers (HR 0.85, 95% CI 0.70, 1.05; Ptrend = 0.35; Pinteraction = 0.0009) and remained in analyses restricted to cases diagnosed >10 years after baseline (HR 0.65, 95% CI 0.51, 0.82; Ptrend = 0.0005). Associations were similar between subgroups who drank predominately caffeinated or decaffeinated coffee (Pinteraction = 0.74)., Conclusion: In this investigation of coffee and RCC, to our knowledge the largest to date, we observed a 20% reduced risk for intake of ≥2 cups/day vs not drinking. Our findings add RCC to the growing list of cancers for which coffee consumption may be protective., (Published by Oxford University Press on behalf of the International Epidemiological Association 2021. This work is written by US Government employees and is in the public domain in the US.)

The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n = 144) and ccB (n = 106) cases and 1476 controls through case-only and case-control comparisons to assess risk factor differences across subtypes using logistic and polytomous regression models. We also performed a meta-analysis summarizing case-only results from our study and three patient cohorts. Patients with ccB tumors had poorer survival than those with ccA tumors and were more likely to be male (case-only odds ratio [OR] 2.68, 95% confidence interval [CI] 1.43-5.03). In case-control analyses, body mass index was significantly associated with ccA tumors (OR 2.45, 95% CI 1.18-5.10 for ≥35 vs <25 kg/m 2 ) but not with ccB tumors (1.52, 0.56-4.12), while trichloroethylene was associated with ccB but not ccA (OR 3.09, 95% CI 1.11-8.65 and 1.25, 0.36-4.39 respectively for ≥1.58 ppm-years vs unexposed). A polygenic risk score of genetic variants identified from genome-wide association studies was associated with both ccA and, in particular, ccB (OR 1.82, 1.11-2.99 and 2.87, 95% CI 1.64-5.01 respectively for 90th vs 10th percentile). In a meta-analysis of case-only results including three patient cohorts, we still observed the ccB excess for male sex and the ccA excess for obesity. In conclusion, our findings suggest the existence of etiologic heterogeneity across ccRCC molecular subtypes for several risk factors., (© 2021 Union for International Cancer Control. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population., Methods: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided., Results: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy., Conclusions: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical., (Published by Oxford University Press 2020.)

Purpose: Renal cell carcinoma (RCC) incidence is higher among black than white Americans. The reasons for this disparity remain unclear., Methods: We calculated race- and sex-specific population attributable risk percentages (PAR%) and their 95% confidence intervals (CI) for hypertension and chronic kidney disease (CKD) among black and white subjects ≥  50 years of age from the US Kidney Cancer Study (USKC; 965 cases, 953 controls), a case-control study in Chicago and Detroit, and a nested case-control study in the Kaiser Permanente Northern California health care network (KPNC; 2,162 cases, 21,484 controls). We also estimated PAR% for other modifiable RCC risk factors (cigarette smoking, obesity) in USKC., Results: In USKC, the PAR% for hypertension was 50% (95% CI 24-77%) and 44% (95% CI 25-64%) among black women and men, respectively, and 29% (95% CI 13-44%) and 27% (95% CI 14-39%) for white women and men, respectively. In KPNC, the hypertension PAR% was 40% (95% CI 18-62%) and 23% (95% CI 2-44%) among black women and men, and 27% (95% CI 20-35%) and 19% (95% CI 14-24%) among white women and men, respectively. The PAR% for CKD in both studies ranged from 7 to 10% for black women and men but was negligible (<1%) for white subjects. In USKC, the PAR% for current smoking was 20% and 8% among black and white men, respectively, and negligible and 8.6% for black and white women, respectively. The obesity PAR% ranged from 12 to 24% across all race/sex strata., Conclusions: If the associations found are causal, interventions that prevent hypertension and CKD among black Americans could potentially eliminate the racial disparity in RCC incidence (hypothetical black:white RCC incidence ratio of 0.5).

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

Objectives: Lead is a suspected carcinogen that has been inconsistently associated with kidney cancer. To clarify this relationship, we conducted an analysis of occupational lead exposure within a population-based study of kidney cancer using detailed exposure assessment methods., Methods: Study participants (1217 cases and 1235 controls), enrolled between 2002 and 2007, provided information on their occupational histories and, for selected lead-related occupations, answered questions regarding workplace tasks, and use of protective equipment. Industrial hygienists used this information to develop several estimates of occupational lead exposure, including probability, duration and cumulative exposure. Unconditional logistic regression was used to compute ORs and 95% CIs for different exposure metrics, with unexposed subjects serving as the reference group. Analyses were also conducted stratifying on several factors, including for subjects of European ancestry only, single nucleotide polymorphisms in ALAD (rs1805313, rs1800435, rs8177796, rs2761016), a gene involved in lead toxicokinetics., Results: In our study, cumulative occupational lead exposure was not associated with kidney cancer (OR 0.9, 95% CI 0.7 to 1.3 for highest quartile vs unexposed; p trend =0.80). Other lead exposure metrics were similarly null. We observed no evidence of effect modification for the evaluated ALAD variants (subjects of European ancestry only, 662 cases and 561 controls) and most stratifying factors, although lead exposure was associated with increased risk among never smokers., Conclusions: The findings of this study do not offer clear support for an association between occupational lead exposure and kidney cancer., Competing Interests: Competing interests: PAS is employed by Stewart Exposure Assessments, LLC (Arlington, Virginia, USA). The remaining authors declare they have no actual or potential competing financial interests., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation., Methods and Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose., Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TE declared employment, research support, and stock in AstraZeneca and research support from Bayer and Pfizer. PCH is a population health fellow of Cancer Research UK. GDS is a member of the Editorial Board of PLOS Medicine.

Background: We developed a systematic, data-driven approach to estimate metrics of occupational exposure to lead to aid in epidemiologic analyses in a case-control study of kidney cancer., Methods: Probability of exposure to ten lead sources was assigned using decision rules developed from an extensive literature review and expert judgement. For jobs with >50% probability of exposure, we assigned source-specific frequency based on subjects' self-reported task frequencies or means of subjects' job-groups and source-specific intensity estimates of blood lead (μg/dL)., Results: In our study, 18.7% of employed person-years were associated with high (≥80%) probability of exposure to any lead source. The most common medium (>50%) or high probability source of lead exposure was leaded gasoline (2.5% and 11.5% of employed person-years, respectively). The median blood lead attributed to occupational exposure was 3.1 μg/dL., Conclusions: These rules can aid in future studies after population-specific adaption for geographic differences and different exposure scenarios., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Although obesity is an established risk factor for renal cell carcinoma (RCC), it is unclear whether this relationship varies across histologic subtypes., Methods: We conducted a nested case-control study within the Kaiser Permanente Northern California (KPNC) health care network, and meta-analysis combining our results with those of previously published studies. Our KPNC study included 685 RCC cases [421 clear cell; 65 papillary; 24 chromophobe; 35 other; 141 not otherwise specified (NOS)] and 4266 controls. Subtype-specific odds ratios (ORs) and 95% confidence intervals (CIs) for categories of body mass index (BMI) and were computed from the case-control data using polytomous logistic regression. Findings from this and other relevant studies were combined by meta-analysis using a random effects model., Results: In the KPNC study, obesity (BMI ≥ 30 kg/m 2 ) was associated with clear cell RCC (OR 1.5, 95% CI 1.1-2.1) and chromophobe RCC (OR 2.5, 95%CI 0.8-8.1), but not with papillary RCC (OR 1.0, 95% CI 0.5-1.9). In meta-analysis including three additional studies, a similar pattern of summary relative risks (SRR) for obesity was observed across subtypes (clear cell: SRR 1.8, 95% CI 1.5-2.2; chromophobe: SRR 2.2, 95% CI 1.3-3.7; papillary, SRR 1.2, 95% CI 0.8-1.6)., Conclusions: These findings support the hypothesis that histologic subtypes of RCC possess distinct etiologic pathways, with obesity important for the development of clear cell and, possibly, chromophobe RCC, but not papillary RCC., (Published by Elsevier Ltd.)

Kidney cancer incidence in African Americans (AA) is higher than among European Americans (EA); reasons for this disparity are not fully known. Dietary micronutrients may have a protective effect on renal cell carcinoma (RCC) development by inhibiting oxidative DNA damage and tumor growth. We evaluated whether any micronutrient associations differed by race in the US Kidney Cancer Study. 1142 EA and AA RCC cases and 1154 frequency-matched controls were enrolled in a population-based case-control study between 2002 and 2007. Dietary micronutrient intake was derived from an interviewer-administered diet history questionnaire. RCC risk associated with micronutrient intake was estimated using adjusted odds ratios from logistic regression comparing lower to highest quartiles of intake and sample weighting. Inverse associations with RCC risk were observed for α-carotene, β-carotene, lutein zeaxanthin, lycopene, vitamin A, folate, thiamin, vitamin C, α-tocopherol, β-tocopherol, γ-tocopherol, and selenium. A trend for β-cryptoxanthin was suggested among EA but not AA or the total sample (P-interaction = .04). Otherwise, findings did not differ by race, gender, age, or smoking status. The increase in RCC risk associated with lower micronutrient intake is similar within AA and EA populations. A diet rich in sources of micronutrients found in fruits, vegetables, and nuts may help to reduce the overall risk of RCC., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings., Objective: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations., Design, Setting, and Participants: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length., Outcome Measurements and Statistical Analysis: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis., Results and Limitations: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R 2 >0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13)., Conclusions: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk., Patient Summary: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma., (Published by Elsevier B.V.)

Objective: To investigate differences between Hispanics and non-Hispanic whites diagnosed with and treated for renal cell carcinoma in an equal access healthcare system., Methods: We carried out a retrospective cohort study within the Kaiser Permanente healthcare system using records from renal cell carcinoma cases. Ethnicity was identified as Hispanic or non-Hispanic whites. Patient characteristics, comorbidities, tumor characteristics and treatment were compared. Overall and disease-specific survival was calculated, and a Cox proportion hazard model estimated the association of ethnicity and survival., Results: A total of 2577 patients (2152 non-Hispanic whites, 425 Hispanic) were evaluated. Hispanics were diagnosed at a younger age (59.6 years vs 65.3 years). Clear cell renal cell carcinoma was more prevalent, whereas papillary renal cell carcinoma was less common among Hispanics. Hispanics had a lower American Joint Committee on Cancer stage (I/II vs III/IV) than non-Hispanic whites (67.4% vs 62.2%). Hispanics were found to have a greater frequency of comorbidities, such as chronic kidney disease and diabetes, but were more likely to receive surgery. The presence of metastases, nodal involvement, increased tumor size, non-surgical management, increasing age and Hispanic ethnicity were independent predictors of worse cancer-specific outcome., Conclusions: Within an equal access healthcare system, Hispanics seem to be diagnosed at younger ages, to have greater comorbidities and to present more frequently with clear cell renal cell carcinoma compared with non-Hispanic white patients. Despite lower stage and greater receipt of surgery, Hispanic ethnicity seems to be an independent predictor of mortality. Further work is necessary to confirm these findings., (© 2017 The Japanese Urological Association.)

Background: Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection. Methods: We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk. Results: In the discovery phase, 32,946 SNPs located at ±10 kb of 2,001 obesity-related genes were extracted from MDA RCC GWAS and analyzed using multivariable logistic regression. Proxies ( R 2 > 0.8) were searched or imputation was performed if SNPs were not directly genotyped in the validation sets. Twenty-one SNPs with P < 0.05 in both MDA RCC GWAS and NCI RCC GWAS were subsequently evaluated in MDA RCC OncoArray. In the overall meta-analysis, significant ( P < 0.05) associations with RCC risk were observed for SNP mapping to IL1RAPL2 [rs10521506-G: OR meta = 0.87 (0.81-0.93), P meta = 2.33 × 10 -5 ], PLIN2 [rs2229536-A: OR meta = 0.87 (0.81-0.93), P meta = 2.33 × 10 -5 ], SMAD3 [rs4601989-A: OR meta = 0.86 (0.80-0.93), P meta = 2.71 × 10 -4 ], MED13L [rs10850596-A: OR meta = 1.14 (1.07-1.23), P meta = 1.50 × 10 -4 ], and TSC1 [rs3761840-G: OR meta = 0.90 (0.85-0.97), P meta = 2.47 × 10 -3 ]. We did not observe any significant cis-expression quantitative trait loci effect for these SNPs in the TCGA KIRC data. Conclusions: Taken together, we found that genetic variation of obesity-related genes could influence RCC susceptibility. Impact: The five identified loci may provide new insights into disease etiology that reveal importance of obesity-related genes in RCC development. Cancer Epidemiol Biomarkers Prev; 26(9); 1436-42. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Leukocyte telomere length (LTL) is a potential biomarker of cancer prognosis; however, evidence for renal cell carcinoma (RCC) is inconsistent., Methods: We investigated LTL and RCC-specific survival among 684 cases from the US kidney cancer study (USKC) and 241 cases from the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO). Leukocyte telomere length was measured by quantitative polymerase chain reaction, and hazard ratios (HRs) and 95% confidence intervals (CIs) computed using multivariable Cox models., Results: Short LTL was associated with poorer disease-specific survival in both USKC (lowest vs highest quartile: HR: 2.3, 95% CI: 1.2-4.4; P for trend=0.02) and PLCO (HR: 2.4, 95% CI: 1.0-5.4; P=0.04). Among USKC cases, the association was strongest for stage-I RCC (HR: 5.5, 95% CI: 1.6-19.0; P=0.006)., Conclusions: Our findings suggest that shorter LTL is an independent marker of poor RCC prognosis, particularly for stage-I disease.

Purpose: Obesity is an established risk factor for renal cell carcinoma (RCC). It is unclear what biologic mechanisms underlie this association, although recent evidence suggests that the effects of circulating hormones such as insulin-like growth factors (IGF) and adipokines may play a role., Methods: To address this question, we conducted a nested case-control study of RCC (252 cases, 252 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial investigating associations with pre-diagnostic serum levels of total adiponectin, high-molecular-weight (HMW) adiponectin, IGF-1, IGF-binding protein-3 (IGFBP-3), and C-peptide. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using conditional logistic regression., Results: After adjustment for potential confounders, non-significant associations with RCC were observed for total adiponectin (OR for highest vs. lowest quartile = 0.65, 95% CI 0.37-1.14; p trend  = 0.35), HMW adiponectin (0.67, 0.38-1.17; p trend  = 0.36), IGF-1 (1.35, 0.77-2.39; p trend  = 0.17), IGFBP-3 (1.47, 0.83-2.62; p trend  = 0.53), and C-peptide (1.52, 0.86-2.70; p trend  = 0.15). In a joint analysis with body mass index (BMI, kg/m 2 ), obese individuals (BMI ≥30) with above-median levels of IGFBP-3 had a significantly higher risk versus those with BMI <25 and below-median IGFBP-3 (OR 2.42, 1.11-5.26), whereas obese individuals with low IGFBP-3 did not (1.18, 0.53-2.64) (p interaction  = 0.35)., Conclusions: The results of this study, while not clearly supporting associations with these obesity-related hormones, suggest that the association between obesity and RCC may be partially modified through mechanisms related to elevated IGFBP-3.

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

Purpose: Use of antihypertensive medications has been associated with renal cell carcinoma (RCC), but it is unclear whether specific types of medications increase RCC risk independent of the effect of hypertension, or whether the association varies by histologic subtype. To address this question, we analyzed data from a U.S. population-based case-control study of RCC., Methods: We collected information on participants' use of drugs to treat hypertension, heart problems, weight control, and swelling. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for each of four major drug classes, separately for participants with (643 cases, 443 controls) and without (500 cases, 718 controls) a history of hypertension, using unconditional logistic and polytomous regression models., Results: None of the antihypertensive drug types was associated with RCC overall. Among participants with a history of hypertension, papillary RCC was associated with long-term use of diuretics (OR = 3.1, 95% CI = 1.4-6.7 for 16+ years, 16 cases, 31 controls; P-trend = 0.014) and calcium channel blockers (OR = 2.8, 95% CI = 1.1-7.4 for 16+ years, 8 cases, 14 controls; P-trend = 0.18), while corresponding ORs for clear cell RCC were weaker (ORs 0.9 and 1.5, respectively) and nonsignificant. The only significant finding among those with no hypertension history was an association between calcium channel blockers and papillary RCC (OR = 17.9, 95% CI = 5.9-54.5) that was based on small numbers (8 cases, 9 controls). There was little evidence of an association between RCC and use of ACE inhibitors or beta blockers., Conclusions: Our study, while inconclusive for overall RCC, provides, to our knowledge, the first evidence supporting an association between antihypertensive medications and papillary RCC. These subtype-specific findings, although based on small numbers, warrant further investigation.

Objectives: Trichloroethylene, a chlorinated solvent widely used for metal degreasing, is classified by the International Agency for Research on Cancer as a kidney carcinogen. Other chlorinated solvents are suspected carcinogens, most notably the cleaning solvent perchloroethylene, although it is unclear whether they are associated with kidney cancer. We investigated kidney cancer associations with occupational exposure to 6 chlorinated solvents (trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, carbon tetrachloride, chloroform, and methylene chloride) within a case-control study using detailed exposure assessment methods., Methods: Cases (n=1217) and controls (n=1235) provided information on their occupational histories and, for selected occupations, on tasks involving potential exposure to chlorinated solvents through job-specific interview modules. Using this information, an industrial hygienist assessed potential exposure to each solvent. We computed ORs and 95% CIs for different exposure metrics, with unexposed participants as the referent group., Results: 1,1,1-trichloroethane, carbon tetrachloride, chloroform, and methylene chloride were not associated with kidney cancer. Among jobs with high exposure intensity, high cumulative hours exposed to perchloroethylene was associated with increased risk, both overall (third tertile vs unexposed: OR 3.1, 95% CI 1.3 to 7.4) and after excluding participants with ≥50% exposure probability for trichloroethylene (OR 3.0, 95% CI 0.99 to 9.0). A non-significant association with high cumulative hours exposed to trichloroethylene was observed (OR 1.7, 95% CI 0.8 to 3.8)., Conclusions: In this study, high exposure to perchloroethylene was associated with kidney cancer, independent of trichloroethylene. Additional studies are needed to further investigate this finding., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Analgesics are the most commonly consumed drugs worldwide. Evidence that analgesics increase kidney cancer risk has been mixed. We investigated the association between renal cell carcinoma (RCC) and analgesic use in a large population-based case-control study and a post-trial observational cohort study. Findings were used to update a recent meta-analytic review. We analyzed data from 1,217 RCC cases and 1,235 controls in the US Kidney Cancer Study and 98,807 participants in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO: n = 137 RCCs). Self-reported acetaminophen, aspirin and nonsteroid anti-inflammatory drug (NSAID) use and duration information was assessed in relation to RCC. For the US Kidney Cancer Study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. For PLCO, we computed hazard ratios (HRs) and 95%CIs using Cox regression. Among case-control participants, RCC risk was associated with over-the-counter acetaminophen use (OR = 1.35, 95%CI = 1.01-1.83). There was a positive trend with increasing duration (p-trend = 0.01), with a two-fold risk for use ≥10 years (OR = 2.01, 95%CI = 1.30-3.12). No association with prescription acetaminophen use was detected. In PLCO, acetaminophen use was also associated with increased RCC risk (HR = 1.68, 95%CI = 1.19-2.39), although elevated risk was absent among the few long-term users. No association with RCC risk was detected for aspirin or NSAIDs use in either study. An association between acetaminophen use and kidney cancer was supported by meta-analytic cohort (n = 4; summary relative risk = 1.34; 95%CI = 1.13-1.59; p-heterogeneity  = 0.40) and case-control (n = 9, summary OR = 1.20; 95%CI = 1.01-1.42; p-heterogeneity  = 0.05) findings. In brief, acetaminophen use may increase the risk of developing RCC., (© 2016 UICC.)

Epidemiological evidence of a relationship between vitamin D and kidney cancer risk has been inconsistent despite experimental data indicating that vitamin D and its metabolites may inhibit carcinogenesis. Previously we reported an inverse association between renal cell carcinoma (RCC) risk and occupational ultraviolet (UV) exposure among European men. In this study, we examined the association between occupational UV exposure and RCC risk among US residents and investigated whether this association varied by race and sex. Lifetime occupational data for 1,217 RCC cases and 1,235 controls in a population-based case-control study, conducted from 2002 to 2007, were assessed for occupational UV exposure. We evaluated exposure metrics in quartiles based on control exposure levels and calculated associations between RCC risk and occupational UV exposure using unconditional logistic regression adjusted for sex, race, body mass index, smoking, hypertension, center, education, family history of cancer and dietary vitamin D intake. A general pattern of decreasing RCC risk with increasing UV exposure was observed. Cases had significantly lower cumulative occupational UV exposure than controls (fourth quartile vs. first: odds ratio = 0.74 [95% confidence interval = 0.56-0.99], p-trend = 0.03). Similar results were observed for other UV exposure metrics. The association with occupational UV exposure was stronger for women than for men, but did not differ by race. Our findings suggest an inverse association between occupational UV exposure and RCC, particularly among women. Given the sex finding discrepancies in this study versus our previous study, additional research is need to clarify whether the protective effects of occupational UV exposure and RCC risk are real., (© 2015 UICC.)

We examined the overall survival of a population-based cohort of black and white patients with renal cell carcinoma (RCC) to better understand the paradox of poorer RCC survival despite more frequent diagnosis at lower stage among blacks. Renal cell carcinoma patients (699 white, 252 black) diagnosed between 2002 and 2007 in metropolitan Detroit were followed for vital status in the Detroit Surveillance, Epidemiology and End Results (SEER) registry. Hazard ratios (HR) of death for black versus white race and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models stratified by demographic and prognostic factors, and in models successively adjusted for clinical factors, comorbidities, and socioeconomic factors. Mean follow-up time was 88.4 months for white patients and 89.6 months for black patients (P = 0.49), with 202 white deaths and 89 black deaths (P = 0.06). While black race was weakly associated with poorer overall survival (P = 0.053), black patients <65 years at diagnosis or with tumors <4 cm in size had significantly poorer survival than their white counterparts (HR = 1.46, 95% CI 1.06-2.01 and HR = 2.15, 95% CI 1.51-3.06, respectively). The racial disparities within these two subgroups were minimally affected by adjustment for clinical/treatment factors (HR = 1.49, 95% CI 1.01-2.19 and HR = 1.95, 95% CI 1.27-2.99), but were substantially reduced when renal-relevant comorbidities were added (HR = 1.30, 95% CI 0.89-1.91 and HR = 1.76, 95% CI 1.16-2.66). After further adjustment for socioeconomic factors, the survival disparities were essentially null (HR = 1.14, 95% CI 0.71-1.85 and HR = 1.15, 95% CI 0.67-1.98). In this population-based sample of RCC patients, younger black patients and those with small tumors had poorer overall survival than whites. The disparity was explained primarily by racial differences in renal-relevant comorbidities, particularly chronic renal failure, and socioeconomic deprivation. Future research should focus on younger patients and those with smaller tumors to better understand how these factors may contribute to the survival disparity., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Recent epidemiological studies suggest that alcohol consumption may reduce renal cell carcinoma (RCC) risk, although inconsistent findings have been reported by sex and alcoholic beverage type. To better understand the relationship between alcohol consumption and RCC risk, we conducted an analysis within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We followed up participants in the analytic cohort (N = 107,998) through 2010 for incident RCC (N = 408), and computed hazard ratios (HRs) and 95% confidence intervals (CIs) for alcohol intake using Cox regression with adjustment for age, sex, race, study center, hypertension, body mass index, and smoking status. In this study population increasing alcohol consumption was associated with reduced RCC risk compared to non-drinkers (>9.75 g day(-1) : HR, 0.67; 95%CI, 0.50 to 0.89; p trend = 0.002). We observed similar patterns of association for men and women as well as by alcohol beverage type. In analyses stratified by smoking status, the inverse association with consumption was apparent for ever smokers (HR, 0.51; 95%CI, 0.36 to 0.73; p trend<0.0001) but not among never smokers (HR, 1.08; 95%CI, 0.66 to 1.76; P trend = 0.78; p interaction = 0.01). Our study findings offer further support that alcohol consumption is associated with reduced RCC risk, regardless of sex or alcoholic beverage type. The finding of interaction with smoking is novel and requires confirmation., (Published 2014. This article is a US Government work and, as such, is in the public domain of the United States of America.)

So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.

We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (P(meta-analysis) = 9.15 × 10⁻⁴, P(heterogeneity) = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = -0.59, p = 5.61 × 10⁻⁶). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.

Higher levels of LINE1 methylation in blood DNA have been associated with increased kidney cancer risk using post-diagnostically collected samples; however, this association has never been examined using pre-diagnostic samples. We examined the association between LINE1 %5mC and renal cell carcinoma (RCC) risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (215 cases/436 controls), and the Alpha-tocopherol, Beta-carotene Cancer Prevention Study (ATBC) of Finnish male smokers (191 cases/575 controls). Logistic regression adjusted for age at blood draw, study center, pack-years of smoking, body mass index, hypertension, dietary alcohol intake, family history of cancer, and sex was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) using cohort and sex-specific methylation categories. In PLCO, higher, although non-significant, RCC risk was observed for participants at or above median methylation level (M2) compared to those below the median (M1) (OR: 1.37, 95% CI: 0.96-1.95). The association was stronger in males (M2 vs. M1, OR: 1.54, 95% CI: 1.00-2.39) and statistically significant among male smokers (M2 vs. M1, OR: 2.60, 95% CI: 1.46-4.63). A significant interaction for smoking was also detected (P-interaction: 0.01). No association was found among females or female smokers. Findings for male smokers were replicated in ATBC (M2 vs. M1, OR: 1.31, 95% CI: 1.07-1.60). In a pooled analysis of PLCO and ATBC male smokers (281 cases/755 controls), the OR among subjects at or above median methylation level (M2) compared to those below the median (M1) was 1.89 (95% CI: 1.34-2.67, P-value: 3 x 10(-4)); a trend was also observed by methylation quartile (P-trend: 0.002). These findings suggest that higher LINE1 methylation levels measured prior to cancer diagnosis may be a biomarker of future RCC risk among male smokers.

Background: The incidence of renal cell carcinoma in the United States differs by race/ethnicity. To better understand these disparities, we conducted a nested case-control study investigating renal cell carcinoma risk factors across racial/ethnic groups within the Kaiser Permanente Northern California health care network., Methods: Our study included 3136 renal cell carcinoma cases (2152 whites, 293 blacks, 425 Hispanics, and 255 Asians) diagnosed between 1998 and 2008 and 31031 individually matched controls (21478 whites, 2836 blacks, 4147 Hispanics, and 2484 Asians). Risk of renal cell carcinoma was assessed in relation to smoking status, body mass index (BMI), hypertension, and chronic kidney disease. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, and population attributable risk (PAR) to estimate by race the proportion of cases attributable to hypertension and chronic kidney disease., Results: The association between chronic kidney disease and renal cell carcinoma differed markedly by race (Pinteraction < 0.001), with associations observed among blacks (OR = 10.4 [95% CI = 6.0-17.9]), Asians (5.1 [2.2-11.7]), and Hispanics (2.3 [1.1-4.6]) but not whites (1.1 [0.6-1.9]). Hypertension, high BMI, and smoking were associated with renal cell carcinoma, but findings generally did not differ by race. Relative to other racial/ethnic groups, blacks had the highest proportion of renal cell carcinoma incidence attributable to hypertension and chronic kidney disease (combined, PAR = 37%; hypertension only, PAR = 27%; chronic kidney disease, PAR = 10%)., Conclusions: Our findings suggest that hypertension and chronic kidney disease likely have contributed to the observed excess in renal cell carcinoma incidence among blacks compared with whites.

Mitochondrial DNA (mtDNA) is vulnerable to mutations, and the number of copies of mtDNA per cell may increase to compensate for DNA damage. Case-control studies have reported associations between altered mtDNA copy number and risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively. We conducted a nested case-control study (252 cases and 504 controls) of RCC risk in relation to pre-diagnostic leukocyte mtDNA copy number in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. mtDNA copy number was measured in triplicate using a fluorescence-based quantitative PCR assay; samples from 22 cases and 36 controls could not be assayed, leaving 230 cases and 468 controls for analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. High mtDNA copy number was associated with an increased risk of RCC, both overall (highest quartile versus lowest: OR = 2.0, 95% CI = 1.2-3.2; P trend = 0.002) and among cases diagnosed ≥6 years after blood collection (OR = 2.6, 95% CI = 1.4-5.0; P trend = 0.003). These findings did not differ significantly by sex, body mass index, history of hypertension or smoking status (P interaction ≥ 0.3). Results of this study suggest that high pre-diagnostic leukocyte mtDNA copy number, a suspected marker of oxidative DNA damage and mitochondrial dysfunction, is associated with increased future RCC risk.

Recent cohort findings suggest that women who underwent a hysterectomy have an elevated relative risk of kidney cancer, although evidence from past studies has been inconsistent. We conducted a systematic review and meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence investigating hysterectomy and kidney cancer. Studies published from 1950 through 2012 were identified through a search of PubMed and of references from relevant publications. Meta-analyses were conducted using random-effects models to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for hysterectomy, age at hysterectomy (<45, 45+ years) and time since hysterectomy (<10, 10+ years). The SRR for hysterectomy and kidney cancer for all published studies (seven cohort, six case-control) was 1.29 (95% CI, 1.16-1.43), with no evidence of between-study heterogeneity or publication bias. The summary effect was slightly weaker, although still significant, for cohorts (SRR, 1.26; 95% CI, 1.11-1.42) compared with case-control findings (1.37; 95% CI, 1.09-1.73) and was observed irrespective of age at hysterectomy, time since the procedure and model adjustment for body mass index, smoking status and hypertension. Women undergoing a hysterectomy have an approximate 30% increased relative risk of subsequent kidney cancer. Additional research is needed to elucidate the biological mechanisms underlying this association., (Published 2013. This article is a US Government work and, as such, is in the public domain of the United States of America.)

Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) in populations of European ancestry have identified four susceptibility loci. No GWAS has been conducted among African Americans (AA), who experience a higher incidence of RCC. We conducted a GWAS in which we analyzed 1,136,723 common single-nucleotide polymorphisms (SNP) among 255 cases and 375 controls of African ancestry, and further investigated 16 SNPs in a replication set (140 cases and 543 controls). The 12p11.23 variant rs10771279, located 77 kb from the European-ancestry RCC marker rs718314, was associated with RCC risk in the GWAS (P = 1.2 × 10(-7)) but did not replicate (P = 0.99). Consistent with European-ancestry findings, the A allele of rs7105934 on 11q13.3 was associated with decreased risk [OR, 0.76, 95% confidence interval (CI), 0.64-0.91; P = 0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07, respectively, among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR, 0.56; P = 7.4 × 10(-7)) and absent for cases of other or unknown histology (OR, 1.02; P = 0.86). Analyses of rs7105934 by subtype among European-ancestry participants from these studies yielded similar findings (ORs 0.69 and 0.92, respectively). This study provides, to our knowledge, the first evidence that rs7105934 is an RCC susceptibility locus among AAs. Our finding that the association with this SNP may be specific to clear-cell RCC is novel and requires additional investigation. Additional investigation of rs10771279 and other suggestive GWAS findings is also needed.

Purpose: The Surveillance, Epidemiology, and End Results (SEER) program is an important epidemiologic research tool to study cancer. No information is available on its pathologic accuracy for renal cell carcinoma (RCC)., Methods: Central pathology review was analyzed as a part of the United States Kidney Cancer Study. Cases previously identified through the Detroit SEER registry were reviewed. The sensitivity and specificity, and positive and negative predictive values were calculated for each SEER-assigned subtype, with the central review assignments used as the reference., Results: Of the 498 cases included in this study, 490 (98.5%) were confirmed to be RCC. The overall agreement for histology was 78.2% (κ = 0.55); however, individual cases were frequently reclassified. The sensitivity and specificity for SEER-assigned clear cell RCC were 79.1% and 88.1%, respectively, when based solely on the ICD-O-3 morphology code 8310 (n = 310), and 99.2% and 80.5% when 8312 (RCC not otherwise specified; n = 41) was also assumed to be clear cell. Although RCC not otherwise specified is frequently grouped with clear cell, only 78.1% had this histology. Assignments of papillary and chromophobe RCC had comparable sensitivities (73.5% and 72.4%, respectively) and specificities (97.5% and 97.6%). Positive predictive values for clear cell (excluding/including 8312), papillary, and chromophobe RCC were 95.5%/93.5%, 85.9%, and 65.6%, respectively., Conclusions: Our findings confirm that nearly all RCC cases are correctly classified in SEER. The positive predictive value was higher for clear cell RCC than for papillary or chromophobe RCC, suggesting that pathologic confirmation may be warranted for studies of non-clear cell tumors., (Published by Elsevier Inc.)

In the United States, renal cell carcinoma (RCC) has rapidly increased in incidence for over two decades. The most common histologic subtypes of RCC, clear cell, papillary, and chromophobe have distinct genetic and clinical characteristics; however, epidemiologic features of these subtypes have not been well characterized, particularly regarding any associations between race, disease subtypes, and recent incidence trends. Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, we examined differences in the age-adjusted incidence rates and trends of RCC subtypes, including analysis focusing on racial differences. Incidence rates increased over time (2001-2009) for all three subtypes. However, the proportion of white cases with clear cell histology was higher than among blacks (50% vs. 31%, respectively), whereas black cases were more likely than white cases to have papillary RCC (23% vs. 9%, respectively). Moreover, papillary RCC incidence increased more rapidly for blacks than whites (P < 0.01) over this period. We also observed that increased incidence of papillary histology among blacks is not limited to the smallest size strata. We observed racial differences in proportionate incidence of RCC subtypes, which appear to be increasing over time; this novel finding motivates further etiologic, clinical, molecular, and genetic studies., (© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: Existing epidemiologic evidence for the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and renal cell carcinoma (RCC) risk is inconsistent., Methods: We investigated the association between the use of aspirin and nonaspirin NSAIDs and RCC risk in the National Institutes of Health-American Association of Retired Persons (AARP) Diet and Health Study, for which 298,468 AARP members free of cancer, aged 50-71 years, completed a survey on use of NSAIDs (1996-1997). Multivariate Cox proportional hazards models were used to estimate the hazard ratio (HR)., Results: The state cancer registry and mortality index linkage identified 1,084 incident RCC cases through 31 December 2006. No statistically significant associations between the use of aspirin or nonaspirin NSAIDs and RCC risk were found. Compared to nonuse of any NSAIDs, the multivariate-adjusted HRs were 0.95 (95 % CI 0.75-1.21) and 0.93 (95 % CI 0.68-1.26) for monthly use of aspirin and nonaspirin NSAIDs, respectively, 0.92 (95 % CI: 0.69-1.23) and 1.11 (95 % CI: 0.76-1.62) for weekly use, 0.87 (95 % CI: 0.69-1.11) and 1.06 (95 % CI: 0.75-1.48) for daily use; and 0.95 (95 % CI 0.78-1.14) for the use of both aspirin and nonaspirin NSAIDs. We found some suggestions of an increased risk of RCC associated with frequent NSAID use among participants who were <63 years and a reduced risk associated with aspirin use among those ≥63 years. No significant associations were found in other stratified analyses by gender, BMI, smoking, history of diabetes, or history of hypertension., Conclusion: RCC risk was not significantly associated with NSAID use overall. The difference in association by age needs to be explored further.

Clinical and experimental findings suggest that female hormonal and reproductive factors could influence kidney cancer development. To evaluate this association, we conducted analyses in 2 large prospective cohorts (the National Institutes of Health-AARP Diet and Health Study (NIH-AARP), 1995-2006, and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), 1993-2010). Cohort-specific and aggregated hazard ratios and 95% confidence intervals relating reproductive factors and kidney cancer risk were computed by Cox regression. The analysis included 792 incident kidney cancer cases among 283,952 postmenopausal women. Women who had undergone a hysterectomy were at a significantly elevated kidney cancer risk in both NIH-AARP (hazard ratio = 1.28, 95% confidence interval: 1.09, 1.50) and PLCO (hazard ratio = 1.41, 95% confidence interval: 1.06, 1.88). Similar results were observed for both cohorts after analyses were restricted to women who had undergone a hysterectomy with or without an oophorectomy. For the NIH-AARP cohort, an inverse association was observed with increasing age at menarche (P for trend = 0.02) and increasing years of oral contraceptive use (P for trend = 0.02). No clear evidence of an association with parity or other reproductive factors was found. Our results suggest that hysterectomy is associated with increased risk of kidney cancer. The observed associations with age at menarche and oral contraceptive use warrant further investigation.

To investigate whether renal cell carcinoma (RCC) histologic subtypes possess different etiologies, we conducted analyses of established RCC risk factors by subtype (clear cell, papillary and chromophobe) in two case-control studies conducted in the United States (1,217 cases, 1,235 controls) and Europe (1,097 cases, 1,476 controls). Histology was ascertained for 706 U.S. cases (58% of total) and 917 European cases (84%) through a central slide review conducted by a single pathologist. For the remaining cases, histology was abstracted from the original diagnostic pathology report. Case-only analyses were performed to compute odds ratios (ORs) and 95% confidence intervals (CI) summarizing subtype differences by age, sex and race. Case-control analyses were performed to compute subtype-specific ORs for other risk factors using polytomous regression. In case-only analyses, papillary cases (N = 237) were older (OR = 1.2, 95% CI = 1.1-1.4 per 10-year increase), less likely to be female (OR = 0.5, 95% CI = 0.4-0.8) and more likely to be black (OR = 2.6, 95% CI = 1.8-3.9) as compared to clear cell cases (N = 1,524). In case-control analyses, BMI was associated with clear cell (OR = 1.2, 95% CI = 1.1-1.3 per 5 kg/m(2) increase) and chromophobe RCC (N = 80; OR = 1.2, 95% CI = 1.1-1.4), but not papillary RCC (OR = 1.1, 95% CI = 1.0-1.2; test versus clear cell, p = 0.006). No subtype differences were observed for associations with smoking, hypertension or family history of kidney cancer. Our findings support the existence of distinct age, sex and racial distributions for RCC subtypes, and suggest that the obesity-RCC association differs by histology., (Copyright © 2013 UICC.)

Background: It has been hypothesized that genomic instability related to telomere dysfunction may contribute to carcinogenesis. There is some evidence from case-control studies suggesting that short leukocyte telomere length may be associated with an increased risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively., Methods: We conducted a nested case-control study (209 cases, 410 controls) of RCC risk in relation to prediagnostic leukocyte telomere length in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. ORs and 95% confidence intervals (CI) were estimated using conditional logistic regression., Results: Leukocyte telomere length was not significantly associated with future risk of RCC (highest quartile vs. lowest: OR, 0.8; 95% CI, 0.5-1.5; Ptrend = 0.6). Analyses stratified by sex, age, and time from blood collection to RCC diagnosis were similarly null., Conclusions: The results of this study, to our knowledge the first prospective investigation of its kind, do not support an association between prediagnostic leukocyte telomere length and risk of RCC., Impact: In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of RCC.

Despite a well-established link between obesity and renal cell carcinoma (RCC), the mechanism through which obesity acts to increase cancer risk is unclear. Adiponectin, leptin and resistin are adipocyte-secreted peptide hormones that may influence RCC development through their demonstrated effects on inflammation, insulin resistance and cell growth and proliferation. We conducted a nested case-control study to evaluate whether prediagnostic serum adiponectin, leptin and resistin levels are associated with RCC risk. This case-control study (273 cases and 273 controls) was nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish male smokers. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using conditional logistic regression models, with analyte levels modeled continuously and categorically (defined using quartiles among controls). High adiponectin levels were significantly associated with reduced RCC risk (Quartile 4 versus Quartile 1: OR = 0.52, 95% CI = 0.30-0.88; P trend = 0.01). This association remained upon additional adjustment for body mass index at blood collection and exclusion of cases diagnosed within the first 2 years of follow-up. In addition, model adjustment for adiponectin resulted in a substantial attenuation of the association between BMI and RCC (OR per 5 kg/m(2) changed from 1.19 to 1.05). No clear associations with RCC were observed for leptin or resistin. Our results suggest that elevated levels of circulating adiponectin are associated with decreased subsequent risk of RCC. These findings provide the strongest evidence to date, suggesting that the association between obesity and RCC is mediated at least in part through the effects of low adiponectin.

Purpose: In the United States, renal cell carcinoma (RCC) incidence is higher among blacks than among whites. Risk of RCC is elevated among end-stage renal disease patients, although no studies have looked at differences by race in the relationship between chronic renal failure and RCC., Methods: We investigated RCC risk in relation to chronic renal failure in a population-based case-control study of blacks and whites in Chicago and Detroit. Data, including information on kidney disease, were collected from interviews with 1,217 RCC cases (361 blacks, 856 whites) and 1,235 controls (523 blacks, 712 whites). Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression., Results: Risk of RCC was increased in relation to chronic renal failure (OR 4.7, 95 % CI 2.2-10.1) and dialysis (OR 18.0, 95 % CI 3.6-91). The association remained after defining exposure as those who had chronic renal failure ≥10 years prior to RCC diagnosis. Chronic renal failure was more strongly associated with RCC among blacks than among whites (OR 8.7, 95 % CI 3.3-22.9 and 2.0, 0.7-5.6, respectively; p (interaction) = 0.03) and among those without a history of diabetes relative to diabetic subjects (OR 8.3, 95 % CI 3.1-22.7 and 1.9, 0.6-5.9, respectively; p (interaction) = 0.03)., Conclusions: These results suggest that chronic renal failure is a strong risk factor for RCC, particularly among black and non-diabetic subjects. Our findings of differences in risk estimates by race, to our knowledge the first such report, require replication.

Background: Obesity is a risk factor for renal cell (or renal) cancer. The increasing prevalence of obesity may be contributing to the rising incidence of this cancer over the past several decades. The effects of early-age obesity and change in body mass index (BMI) on renal cancer have been studied less thoroughly, and the influence of race has never been formally investigated., Methods: Using data gathered as part of a large case-control study of renal cancer (1214 cases and 1234 controls), we investigated associations with BMI at several time points, as well as with height. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression modeling. Race- and sex-stratified analyses were conducted to evaluate subgroup differences., Results: Obesity (BMI ≥ 30 kg/m) early in adulthood (OR = 1.6 [95% CI = 1.1 to 2.4]) and 5 years before diagnosis (1.6 [1.1 to 2.2]) was associated with renal cancer. The association with early-adult obesity was stronger among whites than blacks (test for interaction, P = 0.006), whereas the association with obesity near diagnosis was marginally stronger in women than men (test for interaction, P = 0.08). The strongest association with renal cancer was observed for obese whites both in early adulthood and before interview (2.6 [1.5 to 4.4]); this association was not present among blacks. Estimates of the annual excess rate of renal cancer (per 100,000 persons) attributed to both overweight and obesity (BMI > 25 kg/m) ranged from 9.9 among black men to 5.6 among white women., Conclusion: Obesity, both early and later in life, is associated with an increased risk of renal cancer. The association with early obesity seems to be stronger among whites than blacks.

Background: The role of occupation in the etiology of renal cell carcinoma (RCC) is unclear. Here, we investigated associations between employment in specific occupations and industries and RCC, and its most common histologic subtype, clear cell RCC (ccRCC)., Methods: Between 2002 and 2007, a population-based case-control study of Caucasians and African Americans (1,217 cases; 1,235 controls) was conducted within the Detroit and Chicago metropolitan areas to investigate risk factors for RCC. As part of this study, occupational histories were ascertained through in-person interviews. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating occupation and industry to RCC risk using adjusted unconditional logistic regression models., Results: Employment in the agricultural crop production industry for five years or more was associated with RCC (OR = 3.3 [95% CI = 1.0-11.5]) and ccRCC in particular (OR = 6.3 [95% CI = 1.7-23.3], P for trend with duration of employment = 0.0050). Similarly, RCC risk was elevated for employment of five years or longer in non-managerial agricultural and related occupations (ORRCC = 2.1 [95% CI = 1.0-4.5]; ORccRCC = 3.1 [95% CI = 1.4-6.8]). Employment in the dry-cleaning industry was also associated with elevated risk (ORRCC = 2.0 [95% CI = 0.9-4.4], P for trend = 0.093; ORccRCC = 3.0 [95% CI = 1.2-7.4], P for trend = 0.031). Suggestive elevated associations were observed for police/public safety workers, health care workers and technicians, and employment in the electronics, auto repair, and cleaning/janitorial services industries; protective associations were suggested for many white-collar jobs including computer science and administrative occupations as well employment in the business, legislative, and education industries., Conclusions: Our findings provide support for an elevated risk of RCC in the agricultural and dry-cleaning industries and suggest that these associations may be stronger for the ccRCC subtype. Additional studies are needed to confirm these findings.