DNA Methylation Changes in Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, and Lung Adenocarcinoma

BACKGROUND:Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation. METHODOLOGY/PRINCIPAL FINDINGS:We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer. CONCLUSIONS/SIGNIFICANCE:The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions

Effects of tube voltage and iodine contrast medium on radiation dose of whole-body CT

Background The low-tube-voltage scan generally needs a higher tube current than the conventional 120 kVp to maintain the image noise. In addition, the low-tube-voltage scan increases the photoelectric effect, which increases the radiation absorption in organs. Purpose To compare the organ radiation dose caused by iodine contrast medium between low tube voltage with low contrast medium and that of conventional 120-kVp protocol with standard contrast medium. Material and Methods After the propensity-matching analysis, 66 patients were enrolled including 33 patients with 120 kVp and 600 mgI/kg and 33 patients with 80 kVp and 300 mgI/kg (50% iodine reduction). The pre- and post-contrast phases were assessed in all patients. The Monte Carlo simulation tool was used to simulate the radiation dose. The computed tomography (CT) numbers for 10 organs and the organ doses were measured. The organ doses were normalized by the volume CT dose index, and the 120-kVp protocol was compared with the 80-kVp protocol. Results On contrast-enhanced CT, there were no significant differences in the mean CT numbers of the organs between 80-kVp and 120-kVp protocols except for the pancreas, kidneys, and small intestine. The normalized organ doses at 80 kVp were significantly lower than those of 120 kVp in all organs (e.g. liver, 1.6 vs. 1.9; pancreas, 1.5 vs. 1.8; spleen, 1.7 vs. 2.0) on contrast-enhanced CT. Conclusion The low tube voltage with low-contrast-medium protocol significantly reduces organ doses at the same volume CT dose index setting compared with conventional 120-kVp protocol with standard contrast medium on contrast-enhanced CT. </jats:sec