DNA Methylation Profile of Multistage Progression of Pulmonary Adenocarcinomas: Atypical Adenomatous Hyperplasia, Bronchioloalveolar Carcinoma and Adenocarcinoma
HJ Lee, J-H Chung, B-h Kim, N-Y Cho, GH Kang. Seoul National University College of Medicine, Seoul, Republic of Korea; Korea University College of Medicine, Seoul, Republic of Korea; Seoul National University Bundang Hospital, Seongnam, Republic of Korea
Background: Atypical adenomatous hyperplasia (AAH) is considered as the precursor lesion of pulmonary adenocarcinomas (ADC). However, the epigenetic alterations of the AAH- bronchioloalveolar carcinomas (BAC)-ADC sequence are not clearly established.
Design: We first analyzed the methylaton status at 62 CpG island loci of 10 nonsmall cell lung cancer (NSCLC) tissues and 10 paired normal tissue using MethyLight assay and then chose 18 genes of cancer specific hypermethylation. Consequently, we analyzed the methylaton status at 18 CpG island loci of 20 normal lung tissues, 21 AAHs, 30 BAC, and 60 ADCs using MethyLight assay.
Results: Methylation of more than one CpG island loci was observed in 15 (71.4%) of the 21 AAH, 27 (90%) of the 30 BAC, 59 (98.3%) of the 60 ADC. The mean number of genes methylated was significantly higher in ADC than in AAH and BAC (6 and 2, 3, respectively; p = 0.003). The data shows that a higher prevalence of GATA3 (16%), HOXA1 (37%), RARB (38%), TMEFF (54%) promoter methylation was observed in AAH and BAC showing early carcinogenesis. The genes frequently methylated in ADC were BCL2 (42%), CCND2 (20%), CDH13 (25%), DLEC1 (30%), GRIN2B (27%), HOXA1 (85%), HOXA10 (15%), MT1G (28%), PENK (43%) and RUNX3 (40%). Four different classes of methylation behaviors were found: (a) genes methylated in ADC only (HOXA10), (b) genes with low and similar methylation frequency (0-25%) in three-step lesions (CRABP1, GATA3, ITGA4, RARRES1, SEZ6L and SFRP5), (c) genes with high and similar methylation frequency (35-72%) in three-step lesions (TMEFF2 and RARB), (d) genes showing an increasing tendency with or without fluctuation of the methylation frequency along the progression (BCL2, CCND2, HOXA1, MT1G and RUNX3).
Conclusions: Our results indicate the involvement of epigenetic alterations in the progression of ADC and that aberrant CpG island methylation tend to accumulate along the multistep carcinogenesis. High levels of CpG island hypermethylation of BCL2, CCND2, HOXA1, MT1G or RUNX3 might serve as a potential biological marker for the progression of invasive ADC.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 236, Monday Morning