Abstract
Abstract DNA hypomethylation was the first recognized epigenetic defect in human cancer. Most human cancers display global DNA hypomethylation, which is typically manifested by reduced 5-methyl-2′-deoxycytidine (5mdC) levels and/or reduced methylation of repetitive DNA elements, including LINE-1 sequences. DNA hypomethylation may contribute to oncogenesis by promoting genomic instability and oncogene activation. Little is currently known about global DNA methylation status in normal tissues from cancer patients, or in individuals at elevated cancer risk. Recently, we reported that leukocytes from breast cancer patients show a significant reduction in global DNA methylation as compared to controls (p<0.001) (Choi et al., Carcinogenesis, 30, 1889-97). Similar findings have also been reported in colorectal, head and neck, and bladder cancers. Systemic alterations in DNA methylation could provide a novel means for early cancer detection, particularly in asymptomatic cancers such as ovarian cancer. In the current study, we examined global DNA methylation in leukocytes from ovarian cancer patients. Importantly, ovarian cancer patient leukocytes show global DNA hypomethylation, as assessed by quantitative LINE-1 bisulfite pyrosequencing, as compared to controls (p=0.0146). However, 5mdC levels did not show a significant difference between cases and controls (p=0.1178, 95% CI −0.1091 to 0.9056), and hypomethylation of LINE-1 does not appear to correlate with 5mdC levels. We examined the relationship between LINE-1 methylation in leukocytes and LINE-1 methylation in tumor tissues from matched ovarian cancer patients. Notably, there was not an association between these two tissues, using Pearson correlation (p=0.58, 95% CI −0.292-0.4889). We analyzed LINE-1 methylation in different histological subtypes of ovarian cancer and found a difference between clear cell cases as compared to controls (p<0.05). Cases with endometrioid histology showed significant difference in methylation as compared to serous cases (p<0.05) and all cases combined (p<0.05), but not controls. Currently, we are extending our studies to measure methylation of the Alu repetitive DNA element, which lies within a different sequence context from LINE-1. Furthermore, we are assessing whether LINE-1 methylation is altered in leukocytes from patients at high risk for developing ovarian cancer, using samples obtained from the Gilda Radner Familial Ovarian Cancer Registry. In summary, our studies reveal that LINE-1 sequences are hypomethylated in leukocytes from ovarian cancer patients, and that LINE-1 hypomethylation in leukocytes may be linked to particular disease subtypes. This discovery could lead to the development of novel diagnostics for ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-87.
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