Global 5-Hydroxymethylcytosine Content Is Significantly Reduced in Human Cancers
Michael C Haffner, Alcides Chaux, Alan K Meeker, David M Esopi, Jonathan Gerber, Laxmi G Pellakuru, Antoun Toubaji, Pedram Argani, Christine Iacobuzio-Donahue, Willian G Nelson, George J Netto, Angelo M De Marzo, Srinivasan Yegnasubramanian. Johns Hopkins University, Baltimore, MD
Background: DNA methylation at the 5-position of cytosines (5mC) represents an important epigenetic modification involved in tissue differentiation and is frequently altered in cancer. Recent evidence suggests that 5mC can be converted to 5-hydroxymethylcytosine (5hmC) in an enzymatic process involving members of the TET protein family. Such 5hmC modifications are known to be prevalent in DNA of embryonic stem cells and in the brain, but the distribution of 5hmC in normal and neoplastic tissues has not been rigorously explored.
Design: We developed a robust immunohistochemical detection method to evaluate global 5hmC in formalin fixed paraffin embedded tissues. This technique was used to study the distribution of 5hmC in a large set of normal tissues, pre-invasive lesions and invasive carcinoma.
Results: We found that 5hmC was abundant in the majority of normal adult tissues. Interestingly, 5hmC appeared to track with differentiation in hierarchically organized tissues, with less differentiated cell compartments showing lower 5hmC staining. We furthermore noted a strong difference in 5hmC levels between normal and neoplastic tissues. Pre-invasive lesions showed a significant reduction of 5hmC levels. 5hmC content was further profoundly decreased in invasive carcinoma of the prostate, colon and breast.
Conclusions: Our findings suggest a distinct role for 5hmC in tissue differentiation, and furthermore provide first evidence for its loss in pre-invasive lesions and invasive carcinoma. We therefore hypothesize that alterations of 5hmC might be intimately associated with malignant transformation and could be an early event in tumor progression.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 285, Tuesday Morning