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Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case-Control Study.

ABSTRACT: Genomic DNA hypomethylation is a hallmark of most cancer genomes, promoting genomic instability and cell transformation. In the present study, we sought to determine whether global DNA methylation in peripheral blood is associated with risk of renal cell carcinoma (RCC).A retrospective case-control study consisting of 889 RCC cases and an equal number of age, gender, and ethnicity-matched controls was applied. Global DNA methylation was measured as 5-mC% content. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between DNA methylation level and the risk of RCC.The median 5-mC% was significantly lower in cases than in healthy controls (P< 0.001). In multivariate logistic regression analysis, individuals in the lowest tertile (T1) of 5-mC% had higher risk of RCC with OR of 1.40 (95% CI, 1.06-1.84), compared with individuals in the highest tertile (T3;Pfor trend= 0.02). When stratified by RCC risk factors, associations between hypomethylation and increased RCC risk appeared to be stronger among males (OR, 1.61;Pfor trend= 0.01), younger age (OR, 1.47;Pfor trend= 0.03), never smokers (OR, 1.55;Pfor trend= 0.02), family history of other cancer (OR, 1.64;Pfor trend= 1.22E-03), and late stage (OR, 2.06,Pfor trend= 4.98E-04). Additionally, we observed significant interaction between gender and 5-mC% in elevating RCC risk (Pfor interaction= 0.03).Our findings suggest an association between global DNA hypomethylation and RCC risk. To establish global DNA hypomethylation as a risk factor for RCC, future prospective studies are warranted. This study may provide further understanding of the etiology of RCC tumorigenesis.

SUBMITTER: Mendoza-Perez J

PROVIDER: S-EPMC4834236 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case-Control Study.

Mendoza-Pérez Julia J Gu Jian J Herrera Luis A LA Tannir Nizar M NM Matin Surena F SF Karam Jose A JA Huang Maosheng M Chang David W DW Wood Christopher G CG Wu Xifeng X

Clinical cancer research : an official journal of the American Association for Cancer Research 20151211 8

<h4>Purpose</h4>Genomic DNA hypomethylation is a hallmark of most cancer genomes, promoting genomic instability and cell transformation. In the present study, we sought to determine whether global DNA methylation in peripheral blood is associated with risk of renal cell carcinoma (RCC).<h4>Experimental design</h4>A retrospective case-control study consisting of 889 RCC cases and an equal number of age, gender, and ethnicity-matched controls was applied. Global DNA methylation was measured as 5-m ...[more]

PMID: 26655847

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Project description: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).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.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.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.

Project description:BACKGROUND:DNA hypomethylation has been suggested to cause genomic instability and increase cancer risk. We aimed to test the hypothesis that DNA hypomethylation is associated with increased risk of bladder cancer. METHODS:We measured cytosine methylation (5-mC) content in genomic DNA from blood cells from patients with bladder cancer enrolled in a large case-control study in Spain between Jan 1, 1998, and Dec 31, 2001. Cases were men and women with newly diagnosed and histologically confirmed urothelial carcinoma of the bladder. Controls were selected from patients admitted to the same hospital for diseases or conditions unrelated to smoking or other known risk factors for bladder cancer. Controls were individually matched to cases on age (within 5 years), sex, race, and area of hospital referral. 5-mC content was measured in leucocyte DNA by use of a combination of high-performance capillary electrophoresis, Hpa II digestion, and densitometry. Data on demographics, 34 polymorphisms in nine folate metabolism genes, and nutritional intake of six B vitamins (including folate), alcohol, and smoking were assessed as potential confounders. Relative 5-mC content was expressed as a percentage (%5-mC) with respect to the total cytosine content (the sum of methylated and non-methylated cytosines). The primary endpoint was median %5-mC DNA content. FINDINGS:%5-mC was measured in leucocyte DNA from 775 cases and 397 controls. Median %5-mC DNA was significantly lower in cases (3.03% [IQR 2.17-3.56]) than in controls (3.19% [2.46-3.68], p=0.0002). All participants were subsequently categorised into quartiles by %5-mC content in controls. When the highest quartile of %5-mC content was used as the reference category (Q4), the following adjusted odds ratios (OR) and 95% CI were recorded for decreasing methylation quartiles: OR(Q3) 2.05 (95% CI 1.37-3.06); OR(Q2) 1.62 (1.07-2.44); and OR(Q1) 2.67 (1.77-4.03), p for trend <0.0001. The lowest cancer risk was noted in never smokers in the highest methylation quartile (never smokers in Q4). By comparison with never smokers in the highest quartile, current smokers in the lowest methylation quartile had the highest risk of bladder cancer (Q1: OR 25.51 [9.61-67.76], p for interaction 0.06). In analyses stratified by smoking, hypomethylation was a strong risk factor in never smokers (OR 6.39 [2.37-17.22]). Amount of methylation in controls were not associated with baseline characteristics, micronutrients, or selected genotypes in folate metabolism pathways. INTERPRETATION:For the first time, to our knowledge, we have shown in a large case-control study that leucocyte DNA hypomethylation is associated with increased risk of developing bladder cancer, and this association is independent of smoking and the other assessed risk factors. Amount of global methylation in genomic DNA could provide a useful biomarker of susceptibility to certain cancer types and further research is warranted.

Project description:Obesity is one of modifiable risk factors for clear cell renal cell cancer (ccRCC). We aim to identify the association between obesity-driven biomarkers and ccRCC risk. This is a retrospective, two-phase, case-control study involving 682 cases and 733 controls. Obesity-driven biomarkers [gastric inhibitory polypeptide (GIP), C-peptide, insulin, resistin, adipsin, peptide YY, pancreatic polypeptide, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1, monocyte chemoattractant protein 1, lipocalin2, leptin, adiponectin] were measured using the Milliplex method. Multivariate logistic regression was used to assess the associations between biomarkers and ccRCC risk. Results revealed that GIP, C-peptide, IL-6 and TNF-α levels were consistently distinct between cases and controls. These markers were significantly associated with ccRCC risk in both phases (except C-peptide). In the combined population, compared with individuals with low levels of the biomarkers, individuals with high level of GIP [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.40-0.67] had lower risk, whereas individuals with high levels of C-peptide (OR = 1.46, 95% CI: 1.15-1.87), IL-6 (OR = 2.20, 95% CI: 1.50-3.22), TNF-α (OR = 1.90, 95% CI: 1.49-2.43) had significantly higher risk. Stratified analysis showed consistent associations with ccRCC risk in most subgroups (P < 0.05). The risk score based on the IL-6, TNF-α and GIP was positively associated with ccRCC risk in a dose-response manner (P for trend = 2.18E-13). Data from The Cancer Genome Atlas indicate that insulin signaling, IL-6 signaling and TNF-α signaling were enhanced in tumors. Collectively, our study demonstrates the integrative effect of insulin resistance and inflammation in ccRCC development, which may elucidate the basis of association between obesity and carcinogenesis. Further confirmation in prospective cohort studies are warranted for clinical applications in prevention and precision medicine of ccRCC.

Project description:PurposeSecond primary malignancy (SPM) is challenging for treatment and long-term survival. We sought to investigate the standardized incidence rate (SIR), risk factors, and survival outcomes for SPM after renal cell carcinoma (RCC) treatment.MethodA nested case-control study was designed, we identified all T1-4N0-1M0 RCC patients diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database and followed them for SPM diagnosis for up to 13 years. Patients with SPM diagnosis ≥6 months after treatment of primary T1-4N0-1M0 RCC were identified as the case cohort and SPM-free patients were the control cohort. SIRs and the excess risk were calculated. A competing risks and Cox model were used to evaluate the risk factors of SPM and overall survival (OS).ResultsA cohort of 6,204 RCC patients with SPM were matched with a control group of 31,020 RCC patients without SPM. The median time-to-SPM interval was 54.5 months in RCC patients with SPM diagnosis. Besides, an SPM of T3/4 or/and M1 stage diagnosis was positively associated with a longer time-to-SPM interval. SIR of SPM increased by follow-up time and decreased with age at diagnosis (Pfor all <0.001). SPM in the kidney had the highest SIR (54.6, P <0.001) among all SPMs. Prostate cancer (29.8%) in males and breast cancer (23.5%) in females were the most common SPM. Older age, black ethnicity, male sex, higher family income, papillary RCC, and lower TNM stage were significant risk factors for SPM diagnosis. The proportion of deaths from SPM exceeds that of deaths from RCC 3 years after the first RCC treatment. Patients with SPM and early time-to-SPM interval shortens the OS compared with SPM-free patients. The 5-year OS was 85.9% and 58.9% from the first RCC and the SPM diagnosis, respectively. Besides, patients with low-grade/early-stage SPM could benefit from aggressive surgical treatment for solid tumors.ConclusionsCollectively, our study described the epidemiological characteristics of SPM among RCC survivors and identified the independent predictors of the SPM diagnosis and its survival outcomes. This study highlights the importance of patient education and follow-up after the surgery for RCC.

Dataset Information

Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case-Control Study.

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Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case-Control Study.

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