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Int J Clin Exp Pathol 2(1),21-33;2009

Original Article
Reversibility of Aberrant Global DNA and Estrogen Receptor-α Gene Methylation
Distinguishes Colorectal Precancer from Cancer

Rulong Shen, Lianhui Tao, Yiqing Xu, Shi Chang, James Van Brocklyn and Jian-Xin Gao

Department of Pathology, Division of Hematology and Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH
43210, USA; Xiangya Medical University Hospital, Changsha, Hunan 410008, China

Received 20 March 2008; Accepted with revision 26 March 2008; Available online 20 April 2008

Abstract: Alterations in the global methylation of DNA and in specific regulatory genes are two epigenetic alterations found in cancer. However,
the significance of epigenetic changes for diagnosis and/or prognosis of colorectal cancer have not been established, although it has been
extensively investigated. Recently we have identified a new type of cancer cell called precancerous stem cells (pCSCs) and proposed that
cancer may arise from a lengthy development process of tumor initiating cells (TICs) → pCSCs → cancer stem cells (CSCs) → cancer, which
is in parallel to histological changes of hyperplasia (TICs) → precancer (pCSCs) → carcinoma (CSCs/cancer cells), accompanied by clonal
evolutionary epigenetic and genetic alterations. In this study, we investigated whether aberrant DNA methylation can be used as a biomarker for
the differentiation between premalignant and malignant lesions in the colorectum. The profile of global DNA and estrogen receptor (ER)-α gene
methylation during cancer development was determined by analysis of 5-methylcytosine (5-MeC) using immunohistochemical (IHC) staining,
dot blot analysis or a quantitative gene methylation assay (QGMA). Herein we show that global DNA hypomethylation and ER-α gene
hypermethylation are progressively enhanced from hyperplastic polyps (HPs) → adenomatous polyps (APs) → adenomatous carcinoma
(AdCa). The aberrant methylation can be completely reversed in APs, but not in AdCa by a nonsteroidal anti-inflammatory drug (NSAID)
celecoxib, which is a selective inhibitor of cyclooxygenase-2 (Cox-2), suggesting that the epigenetic alterations between colorectal precancer
(AP) and cancer (AdCa) are fundamentally different in response to anti-cancer therapy. In normal colorectal mucosa, while global DNA
methylation was not affected by aging, ER-α gene methylation was significantly increased with aging. However, this increase did not reach the
level observed in colorectal APs. Taken together, reversibility of aberrant global DNA and ER-α gene methylation distinguishes colorectal
precancer from cancer. (IJCEP803011).

Key Words: Precancer, DNA methylation, colorectal cancer, estrogen receptor-α, nonsteroidal anti-inflammatory drugs, cancer progression,
epigenetic, tumor initiation

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Address all correspondence to: Jian-Xin Gao, MD, PhD, Department of Pathology, Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue
Columbus, Ohio 43210, Phone: 614-247-2341(Office); 614-292-2018 (Lab), Fax: 614-292-7072, E-mail: