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Sensitivity To NNKOAc Is Associated With Renal Cancer Risk

October 29, 2017

UroToday - Cigarette smoking is a major risk factor for renal cell carcinoma (RCC). Cigarette smoke contains a variety of carcinogenic chemicals such as polycyclic aromatic hydrocarbons, aromatic amines, heterocyclic aromatic amines and N-nitrosamines. Among the N-nitrosamines present in cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most abundant and the most potent in terms of carcinogenicity.

DNA damage requires a DNA repair system that will recognize and repair the damage through complex pathways. Failure to repair the DNA damage may lead to genomic instability and subsequent carcinogenesis. DNA damage/repair capacity can be quantified by phenotypic assays such as the mutagen sensitivity assay, host cell reaction and comet assay. Comet assay, also known as single cell gel electrophoresis technique, is a well-established, technically simple, relatively fast and inexpensive functional assay to measure DNA damage at the individual cell level. The comet assay has been shown to be an effective way to measure NNKOAc-induced damage levels.

Therefore in the current study, the authors used the comet assay to assess whether sensitivity to NNKOAc-induced DNA damage was associated with increased risk of RCC in a population-based case-control study among 95 RCC cases and 188 matched controls. RCC cases were recruited from The University of Texas M. D. Anderson Cancer Center in Houston, Texas.

All cases were individuals with newly diagnosed, histologically confirmed RCC and were residents of Texas. Healthy control subjects without a history of cancer, except non-melanoma skin cancer, were identified and recruited using the random digit dialing (RDD) methods. In RDD, randomly selected phone numbers from household were used to contact potential control volunteers in the same residency of cases according to the telephone directory listings. The controls were frequency matched to the cases by age (+5 years), sex, ethnicity and county of residence. All study participants completed a 45-min in-person interview that was administered by M. D. Anderson Cancer Center staff interviewers. The interview elicited information on demographics, smoking history, family history of cancer, occupational history and exposures and medical history. Half of the cases had a BMI of at least 30 compared to 31.91% of controls. Similarly, only 17.89% of cases had a BMI of less than 25 compared to 29.79% of controls (P = 0.007). Among the cases, 56.84% reported history of hypertension as compared to 39.89% in controls (P = 0.007). These data are consistent with literature that obesity and hypertension are risk factors for RCC.

In Comet assay, Olive tail moments were used as a parameter for the level of DNA damage, the higher the tail moments, the higher the DNA damage level. At baseline, the DNA damage was not significantly different between cases and controls (1.08 vs. 1.02, P = 0.112). However, the NNKOAc-induced Olive tail moments were significantly higher in cases than in controls (2.27 vs. 1.76, P = 0.002). When NNKOAc-induced damage were subtracted by baseline DNA damage, the differences remained significant (1.02 vs. 0.78, P = 0.018). Next, the authors analyzed the association between DNA damage levels and risk for RCC. Using the 75th percentile Olive tail moments of the controls as the cutoff point, they found that higher levels of NNKOAc-induced DNA damage were associated with a 2-fold significantly increased risk of RCC (95% Confidence Interval [95% CI], 1.17-3.61). In quartile analysis, there was a dose-response association between NNK-induced damage and risk of RCC. Compared with individuals within the lowest quartile of NNKOAc-induced damage (the 1st quartile), the ORs for the second, third and fourth quartiles were 1.61 (95% CI: 0.69-3.75), 1.77 (95% CI: 0.76-4.09) and 3.00 (95% CI: 1.36-6.62) with a significant trend (P for trend, 0.006).

This is the first study to evaluate the association between DNA repair capacity to NNK-induced damage and RCC risk. Future studies with larger sample sizes are warranted to investigate the association between NNKOAc sensitivity and RCC risk as modified by other risk factors such as cigarette smoking and obesity.

Jessica Clague, Lina Shao, Jie Lin, Shine Chang, Yimin Zhu, Wei Wang, Christopher G. Wood and Xifeng Wu as part of Beyond the Abstract on UroToday

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