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Biomarkers and Early Detection: Cancer Surveillance and Screening

Discovery of a novel vitamin E-related metabolic system depleted from the serum of colon cancer patients.

Phenomenome Discoveries, Inc., Saskatoon, SK, Canada; Genomics Collaborative, A SeraCare Lifesciences Company, Boston, MA

Abstract

B3

The sequence of hallmark genetic events accompanying the progression of normal colonic epithelial cells into full-blown colorectal cancer (CRC) has been well established for over a decade. However, it is also well recognized that CRC may be influenced by other factors, such as low penetrance hereditary mutations, sporadic mutations, diet and other lifestyle factors. Despite the abundance of research focused on the interaction between genetics and environment, little has been done to investigate whether there are any perturbations of underlying endogenous metabolic systems common among individuals with CRC. Using a non-targeted metabolomics strategy to profile 50 normal and 40 CRC-positive serum samples, a family of novel vitamin E-related molecules present in healthy patient serum samples was discovered that were depleted from the serum of the CRC patients. Accurate mass, HPLC-coupled tandem mass spectrometry and NMR were used to elucidate the structures of six of the molecules, which we named -tocoenoic acids. The molecules are structurally related to -tocotrienol but have reduced chroman rings, varying degrees of side-chain saturation, and omega carboxylations. These molecules were not present in tumor or normal adjacent tissue biopsies from any of the CRC patients. The depletion of these metabolites in CRC-positive serum was then validated using a targeted semiquantitative triple quadrupole-based assay to screen over 600 independent samples. That these molecules are closely related to gamma tocotrienol is of high interest in light of the numerous biological roles of tocotrienols as antioxidants and chemopreventatives. These findings represent the framework for future studies examining the biological activity, diagnostic capability and chemopreventative potential of these molecules.