Abstract
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 grams/day: 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.
Keywords: alcohol intake, kidney cancer, cohort
INTRODUCTION
Kidney cancer is the seventh- and ninth-most commonly diagnosed cancer among U.S. men and women, respectively, with an estimated 64,000 cases expected in 2014 [1–3]. Renal cell carcinoma (RCC) of the renal parenchyma accounts for over 80% of all kidney cancers [4]. Established risk factors include male sex, African American race, family history of kidney cancer, cigarette smoking, hypertension, and excess body weight [4].
Recent epidemiological evidence suggests that alcohol intake may be associated with a reduced RCC risk [5–16]. Specifically, some case-control studies have shown an inverse RCC association with increasing consumption of alcohol [5–8], although not all [17–19]. Decreased RCC risk has also been reported in a number of prospective cohort studies, but results have typically been based on small case numbers [11–13]. Limitations of previously published studies have made it difficult to determine whether the association between RCC and alcohol intake differs 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.
MATERIAL and METHODS
Study Identification
The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was conducted to evaluate the effectiveness of selected cancer screening interventions in reducing mortality for the four cancers of interest [20]. Between 1993 and 2001, approximately 155,000 men and women, 55–74 years of age, were enrolled from among ten centers in the U.S. Information on medical, anthropometric, reproductive and lifestyle factors were collected at baseline. In December of 1998, a dietary questionnaire was added to PLCO where detailed nutritional information, including data on alcohol consumption, was gathered from nearly 119,000 participants.
Subject Selection and Cancer Case Ascertainment
Participants were excluded from this analysis if they had not returned the baseline and dietary questionnaire (N=38,166); had questionnaires filled out by proxies (N=8,381); had reported a previous kidney cancer at baseline (N=255); or had missing follow-up data (N=100). Our final analytic population included 107,998 men and women.
PLCO participants were followed up for all cancer diagnoses by annual mailed questionnaire, with subsequent confirmation through medical records. For this analysis, we ascertained incident RCC cases (International Classification of Diseases for Oncology, Second Edition, code C649) through follow-up from the date of dietary questionnaire completion until December 31, 2009. Censoring events included death, loss to follow-up, renal pelvis cancer or kidney cancer in situ diagnosis, or end of follow-up.
Statistical Analysis
The dietary questionnaire collected information on the number of drinks of beer, liquor and wine participants usually consumed per day, per week or per month within the previous 12 months and at different age periods (18–24, 25–39, 40–54, 55 or older). For our investigation, we analyzed data on the usual number of alcohol drinks consumed within the past 12 months. We grouped total intake of alcohol into categories (0, >0–1.75, >1.75–9.75, >9.75 g/day) using tertiles among drinkers as cut points; tertile categories for total alcohol intake correspond to roughly 0, >0 to <1, 1 to <5, and 5+ standard drinks (i.e., 12 ounces of beer, 8 ounces of wine, or 1.5 ounces (or 1 “shot”) of liquor) per week, respectfully [21]. Subsequently, we categorized intake of total beer, liquor and wine using a common cut point (0, >0–0.75, .0.75–2.00, >2.00 g/day) to facilitate comparisons across beverage types; cut points across beverage types correspond to roughly 0, >0 to ⅓, > ⅓ to 1, and >1 standard drink per week, respectfully [21].
All analyses were conducted using SAS statistical software Version 9.1.3. We determined statistical tests to be significant at a two-sided P value <0.05. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) relating risk factors to RCC incidence using Cox proportional hazards models, with attained age (in days) as the time metric. Tests for linear trend of RCC risk with ordinal variables were examined by treating each category as a continuous term (0, 1, 2…) in the models and were based on the Wald statistics. We assessed proportional hazards assumptions by adding interaction terms between age and each of the exposures of interest in Cox models; no evidence of violations against proportionality was found.
Final models were adjusted for sex, body mass index (BMI) (<25, 25–<30, ≥30 kg/m2), physician-diagnosed hypertension status (yes, no), race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and Asian, Native Indian or Alaskan Pacific Islander), and smoking status (never, former, current). We also assessed models adjusting for highest level of education completed (≤11th grade, 12th grade or completed high school, post-high school training other than college, some college, college or post-college graduate); the findings did not appear to influence HR estimates when included as a model covariate, and was thus not adjusted for in the final models.
We also conducted additional analyses for factors related to alcohol intake stratifying by BMI (<25, 25–<30, and ≥ 30 kg/m2), smoking status (never, former, current), and physician-diagnosed hypertension status. To assess heterogeneity across strata, we used the likelihood ratio test to compare models with and without the corresponding interaction term. Additionally, we performed sensitivity analyses to evaluate the possibility of bias introduced by early symptoms of cancer influencing self-reported consumption of alcohol. Analyses excluding the first two years of follow-up after completion of the dietary questionnaire (341 cases remaining) were also performed to assess the potential for bias due to reverse causation.
RESULTS
During the 1,236,486.5 person-years of follow up (average per participant: 11.4 years), we identified 408 RCC cases (266 men, 142 women). Compared to non-drinkers, participants who consumed alcohol had on average a lower age and BMI, a higher education level, and were more likely to be white and to smoke (Supplemental Table 1).
The observed associations with alcohol consumption, overall and by sex, are summarized in Table 1. We found increasing alcohol intake to be associated with a reduced RCC risk, with HRs of 0.98 (95%CI, 0.75 to 1.29), 0.77 (95%CI, 0.58 to 1.02), and 0.67 (95%CI, 0.50 to 0.89) for ≤1.75, 1.76–9.75, and >9.75 grams per day respectively compared to non-drinkers (P trend=0.002). Similar patterns of association were observed for sex-specific and beverage-specific analyses and after excluding the first two years of follow-up (data not shown).
Table 1.
Alcohol Intake and Kidney Cancer Risk Among PLCO dietary Questionnaire Respondents Stratified by Sex, U.S., 1998 to 2010
| Alcohol Intake (grams per day) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Type of Alcohol | None | >0 to 1.75 | >1.75 to 9.75 | >9.75 | |||||
| Cases (n) | Ref. | Cases (n) | HR (95%CI) | Cases (n) | HR (95%CI) | Cases (n) | HR (95%CI) | P trend | |
| Total Intake | |||||||||
| All Participants | 124 | 1.00 | 103 | 0.98 (0.75 to 1.29) | 93 | 0.77 (0.58 to 1.02) | 88 | 0.67 (0.50 to 0.89)* | 0.002 |
| Men | 66 | 1.00 | 54 | 1.09 (0.76 to 1.58) | 74 | 0.93 (0.66 to 1.31) | 72 | 0.72 (0.51 to 1.02) | 0.04 |
| Women | 58 | 1.00 | 49 | 0.86 (0.58 to 1.28) | 19 | 0.51 (0.30 to 0.88)* | 16 | 0.60 (0.33 to 1.08) | 0.02 |
| P Interaction | 0.12 | ||||||||
| >0 to 0.75 | >0.75 to 2.00 | >2.00 | P trend | ||||||
| Beer Intake | |||||||||
| All Participants | 204 | 1.00 | 77 | 0.86 (0.66 to 1.13) | 59 | 0.92 (0.68 to 1.24) | 68 | 0.61 (0.46 to 0.82)* | 0.003 |
| Men | 106 | 1.00 | 50 | 0.86 (0.61 to 1.21) | 51 | 0.93 (0.66 to 1.31) | 59 | 0.56 (0.40 to 0.77)* | 0.001 |
| Women | 89 | 1.00 | 27 | 0.87 (0.57 to 1.34) | 8 | 0.74 (0.36 to 1.54) | 9 | 1.00 (0.50 to 2.01) | 0.60 |
| P Interaction | 0.57 | ||||||||
| Liquor Intake | |||||||||
| All Participants | 204 | 1.00 | 52 | 0.99 (0.73 to 1.35) | 89 | 0.93 (0.72 to 1.20) | 63 | 0.77 (0.58 to 1.04) | 0.11 |
| Men | 123 | 1.00 | 23 | 0.92 (0.59 to 1.44) | 68 | 0.97 (0.72 to 1.31) | 52 | 0.79 (0.56 to 1.09) | 0.22 |
| Women | 81 | 1.00 | 29 | 1.06 (0.69 to 1.63) | 21 | 0.84 (0.51 to 1.37) | 11 | 0.72 (0.38 to 1.38) | 0.29 |
| P Interaction | 0.56 | ||||||||
| Wine Intake | |||||||||
| All Participants | 194 | 1.00 | 121 | 0.87 (0.69 to 1.10) | 37 | 0.93 (0.65 to 1.32) | 56 | 0.74 (0.55 to 1.01) | 0.07 |
| Men | 121 | 1.00 | 76 | 0.92 (0.69 to 1.23) | 2 | 1.07 (0.71 to 1.64) | 42 | 0.87 (0.61 to 1.25) | 0.57 |
| Women | 73 | 1.00 | 45 | 0.79 (0.54 to 1.15) | 10 | 0.67 (0.34 to 1.32) | 14 | 0.52 (0.29 to 0.94)* | 0.02 |
| P Interaction | 0.13 | ||||||||
Abbreviations: CI, confidence interval; BMI, body mass index; HR, hazard ratio; n, number; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; Ref., reference; U.S., United States.
Adjusted for sex, race, hypertension, BMI, smoking status and study center
Information regarding dietary alcohol intake missing from 14 cases (12 male and 2 female).
P to value <0.05.
In this study population, the association with alcohol consumption was found to differ by smoking status at enrollment (Table 2). With increasing consumption, we observed an inverse association for former and current smokers (>9.75 grams/day HR, 0.55; 95%CI, 0.37 to 0.80; P trend=0.001 and HR, 0.31; 95%CI, 0.12 to 0.81; P trend=0.01, respectively) but not among participants who never smoked (HR, 1.08; 95%CI, 0.66 to 1.76; P trend=0.78; P interaction=0.005). Findings for alcohol consumption did not differ by BMI, obesity, diabetes, race, or hypertension (data not shown).
Table 2.
Smoking Status, Total Alcohol Intake and Kidney Cancer Risk Among PLCO dietary Questionnaire Respondents, U.S., 1998 to 2010
| Alcohol Intake (grams per day) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Type of Alcohol | None | >0 to 1.75 | >1.75 to 9.75 | >9.75 | |||||
| Cases (n) | Ref. | Cases (n) | HR (95%CI) | Cases (n) | HR (95%CI) | Cases (n) | HR (95%CI) | P trend | |
| Total Intake | |||||||||
| Never Smoker | 70 | 1.00 | 46 | 1.20 (0.79 to 1.82) | 39 | 1.10 (0.71 to 1.71) | 29 | 1.08 (0.66 to 1.76) | 0.78 |
| Former Smoker | 56 | 1.00 | 43 | 0.80 (0.54 to 1.20) | 46 | 0.62 (0.41 to 0.91)* | 53 | 0.55 (0.37 to 0.80)* | 0.001 |
| Current Smoker | 14 | 1.00 | 14 | 1.03 (0.49 to 2.17) | 8 | 0.56 (0.23 to 1.35) | 6 | 0.31 (0.12 to 0.81)* | 0.01 |
| P Interaction | 0.0045 | ||||||||
| Ever Smoker | 70 | 1.00 | 57 | 0.63 (0.48 to 0.84)* | 54 | 0.61 (0.42 to 0.87)* | 59 | 0.51 (0.36 to 0.73)* | <0.0001 |
| P Interaction | 0.01 | ||||||||
Abbreviations: CI, confidence interval; BMI, body mass index; HR, hazard ratio; n, number; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; Ref., reference; U.S., United States.
Adjusted for sex, race, hypertension, BMI, smoking status and study center
Information regarding dietary alcohol intake missing from 14 cases (12 male and 2 female).
P-value <0.05.
DISCUSSION
In this large prospective cohort study, we observed alcohol consumption to be inversely associated with RCC risk for both men and women and across different alcohol beverage types. Our results are consistent with most previous prospective studies that have examined the effects of light to moderate alcohol consumption and RCC development [9, 10, 14–16]. In a newly published meta-analysis that included three cohort studies and a pooled analysis of 12 prospective studies, alcohol consumption was associated with a significant 29% reduction in RCC risk [9]. Results were similar by sex and significant protective effects were observed across all beverage types [9]. Conversely, in the most recent assessment of alcohol intake and RCC risk, no association was observed among cohort participants residing in Washington State [22]. The results of this cohort however, may have been affected by different regional dietary practices as the authors cautioned participants may have been more health conscious since they had lower drinking habits and higher fruit and vegetable intake.
Several biologic mechanisms have been proposed to potentially play a role in mediating the association between alcohol intake and reduced RCC. Alcohol has been shown to improve insulin sensitivity [14, 23]. Obesity, a known RCC risk factor, increases insulin resistance [23]. Additionally, experimental evidence suggests that insulin-like growth factors may play a role in kidney tumor formation [24]. Alcohol has also been shown to reduce oxidative stress as it contains anti-oxidant phenolic compounds which can remove oxidized carcinogenic agents, reduce lipid peroxidation as well as cell proliferation, and promote apoptosis [14, 23, 25]. Moderate alcohol intake may also lower blood pressure levels [14, 25].
Our finding for a significant interaction between RCC risk, alcohol intake and smoking status has not been previously observed. Smoking was previously reported to modify the association between spirit intake and RCC risk among males in a Finnish smoking cohort in a manner consistent with our findings, but not for consumption of total alcohol or beer intake [26]. Furthermore, in a pooled study of 12 prospective cohorts, smoking was not found to modify associations between alcohol intake and RCC risk [10]. It is unclear what biologic mechanism could account for such interactive effects. One possibility, though speculative, is that if alcohol reduces RCC risk through reductions in blood pressure, insulin resistance, and oxidative stress, and smoking increases these physiologic effects [27], then there is a greater opportunity for an alcohol-induced reduction in RCC risk among smokers than among non-smokers. However, given the small number of cases in some categories in our stratified smoking analysis and the lack of consistent findings in previous studies, this finding from our study should be interpreted with caution.
Strengths of our study include its population-based prospective design, large size, long follow-up time and information on consumption of specific types of alcoholic beverages. While detailed assessment of potential confounding factors were controlled for in analysis, the effects of residual confounding due to inaccurate, limited, and/or self-reported data cannot be ruled out. Likewise, data on other potentially confounding factors, such as socioeconomic status and physical activity were not accounted for; although as a surrogate for socioeconomic status, we did assess the effects of education, which did not appear to confound risk estimates when included as a model covariate. Our reliance on self-reported “usual” alcohol intake is another limitation of our study as data on consumption was neither validated nor measured. However, such misclassification is not unique to cohort studies and would most likely bias associations towards the null.
In summary, our large prospective cohort study offers further evidence that alcohol consumption is associated with reduced RCC risk among both men and women, and irrespective of alcoholic beverage type. Additional studies are needed to help elucidate the underlying biological mechanism responsible for the inverse relationship between alcohol consumption and RCC development.
Supplementary Material
Novelty & Impact Statements.
Our findings suggest that consumption of alcohol is associated with an approximate 30% reduced risk of renal cell carcinoma. Additional studies are needed to investigate the biological mechanism by which intake may reduce renal cell carcinoma risk.
Acknowledgments
This research was supported by the Intramural Research Program of the NCI, Division of Cancer Epidemiology and Genetics, National Institutes of Health. The PLCO research was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS.
Abbreviations
- BMI
body mass index
- CIs
confidence intervals
- HR
hazard ratio
- ICD
international classification of disease
- NIH
National Institutes of Health
- OR
Odds ratio
- PLCO
Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial
- RR
relative risk
- RCC
renal cell carcinoma
- U.S
United States
Footnotes
Author’s disclosures of potential conflicts of interest: non for all authors.
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