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Invited Abstract (Keynote Address): Keynote Address

Molecular detection and monitoring of cancer using tumor-derived DNA in plasma

The Chinese University of Hong Kong, Shatin, Hong Kong

Abstract

KN-02

Recently, much interest has been focused on the use of nucleic acids that are released by tumor cells into the plasma of cancer patients. My group has focused on the use of this approach for cancers which are particularly common in South China, especially nasopharyngeal carcinoma (NPC) and hepatocellular carcinoma (HCC). NPC is a particularly attractive target for this approach because virtually all cases of NPC in South China are associated with Epstein-Barr virus (EBV) infection. We have demonstrated that EBV DNA is present in high concentrations in the plasma of most NPC patients. Furthermore, the concentration of plasma EBV DNA is a powerful prognosticator, both at presentation and following treatment. With regard to the biophysical characterization of circulating EBV DNA, we have shown that these molecules consist of short DNA fragments instead of complete virions. This observation might be related to the mode of release of EBV DNA into the plasma, for example, as a result of tumoral cell death. For HCC, we have focused on the use of aberrant DNA methylation as a tumor marker in plasma.In addition to plasma DNA, my group has also demonstrated that RNA is readily detectable in human plasma. Furthermore, such plasma RNA molecules are surprisingly stable, possibly protected from plasma RNase digestion through association with particulate matter. As a consequence, tumor-derived RNA molecules have been reported by a number of groups in the plasma of cancer patients. Tumor-associated targets which have been reported to date include EBV RNA, tyrosinase mRNA, beta-catenin mRNA, etc. My group has also demonstrated that such plasma RNA molecules are partially degraded, with a predominance of the 5' ends of the molecules. This latter observation is probably a consequence of the fact that most mammalian RNases work from the 3' direction. A measurement of the ratio of concentrations of the 5' and 3' sequences of mRNA in plasma is therefore an indication of plasma RNA integrity. Furthermore, plasma RNA integrity has been found to be decreased in NPC patients and to be normalized following radiotherapy. This latter observation suggests that plasma RNA integrity may be a new tumor marker.The potential functionality of circulating nucleic acids is one area which has been debated, but where no definite empirical answer has emerged to date.