Abstract 4461: A prospective study of blood mitochondrial DNA copy number and risk of renal cell carcinoma

Background: Mitochondrial DNA (mtDNA) is vulnerable to mutations, and the number of copies of mtDNA per cell may increase to compensate for DNA damage. Recent studies have evaluated blood leukocyte mtDNA copy number and risk of various types of cancer, including renal cell carcinoma (RCC). Although alterations in mtDNA copy number have been associated with cancer risk, the direction of this association has been inconsistent between studies with prospective and retrospective blood collection. One case-control study found that low mtDNA copy number was associated with an increased risk of RCC; however, this association has not been investigated prospectively. Methods: We conducted a nested case-control study of RCC risk in relation to mtDNA copy number in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 230 cases and 469 controls matched on age, sex, race, date of blood collection and specimen type were included. Measurements of mtDNA copy number were performed in triplicate using a fluorescence-based QPCR assay. Assay results were highly reproducible, with a coefficient of variation of 5.3% for replicate QC samples from a single individual and an intraclass correlation coefficient of 0.69 for duplicate samples collected an average of 3.6 years apart from 45 controls. To evaluate risk of RCC in relation to mtDNA copy number, we calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression models adjusted for all matching variables as well as history of hypertension, body mass index, smoking history, and family history of kidney cancer. Subjects were assigned to quartiles of mtDNA copy number based on the distribution among controls. Results: Median mtDNA copy number was higher for cases than for controls (131 vs. 121; P=0.001, Wilcoxon rank-sum test). Relative to subjects in the lowest quartile of mtDNA copy number, the ORs for subjects in the 2nd, 3rd, and 4th quartiles were 1.0 (95% CI 0.6-1.6), 1.5 (95% 0.9-2.3), and 1.9 (95% CI 1.2-3.1), respectively (Ptrend = 0.003). The association between mtDNA copy number and RCC was stronger among men (highest vs. lowest quartile, OR 2.4, 95% CI 1.3-4.4) than among women (OR 1.3, 95% CI 0.5-3.2; Pint = 0.24). Results were similar in conditional logistic regression analyses of matched sets, and when we restricted to subjects with mtDNA from buffy coat specimens and to cases diagnosed more than two years after sample collection. Conclusions: Results of this study, to our knowledge the first prospective investigation of mtDNA copy number and RCC risk, suggest that high mtDNA copy number is associated with an increased risk of RCC, particularly among men. Although our findings were inconsistent with prior case-control evidence, most prospective studies of other cancers (e.g., lung, pancreas, non-Hodgkin lymphoma) have reported positive associations. Replication of these findings in other prospective cohorts is needed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4461. doi:1538-7445.AM2012-4461