Madison L. Hannan

Changes in lipid metabolism have been associated with the development of colorectal cancer (CRC), and they may serve as diagnostic markers to identify patients who have developed colorectal neoplasia. This study aimed to identify such biomarkers using untargeted lipidomics. Lipidomics were performed in serum from a racially diverse series of CRC cases and controls from Chicago and Tucson. In addition, enzymatic activity of secretory acid sphingomyelinase (aSMase; S-SMase) was measured in samples from the Tucson CRC series, and two series of adenoma patients. Untargeted lipidomics in the Chicago CRC series revealed significant alterations in sphingolipids. Targeted lipidomics revealed a robust signature of five sphingomyelins (SMs) that were significantly decreased in Chicago CRC patients compared to controls and were validated in the Tucson series. S-SMase activity, which degrades serum SMs, was elevated in CRC cases (0.13 ± 0.10 Cer/SM UACC CRC cases vs. 0.05 ± 0.04 Cer/SM controls; p<0.0001). In mostly white adenoma patients from Tucson, serum S-SMase activity could predict the presence of colorectal neoplasia (0.13 ± 0.07 Cer/SM in UACC adenoma cases vs. 0.03 ± 0.02 Cer/SM in controls; p<0.0001). However, S-SMase activity was not significantly different in Black adenoma patients from Chicago compared to controls. Together, these studies demonstrate for the first time the potential for S-SMase activity to serve as a biomarker for colorectal neoplasia in specific populations.

Background: Metabolomic changes related to colorectal cancer (CRC) may serve as diagnostic markers to identify patients may develop or have developed CRC. Methods: Untargeted lipidomics were performed on serum from CRC cases and clean-colon controls from the Chicago Colorectal Cancer Consortium (CCCC) and the University of Arizona Cancer Center (UACC). Results: Untargeted lipidomics in the CCCC CRC series revealed significant alterations in sphingolipids. Targeted lipidomics revealed a signature of five sphingomyelins (SMs) were significantly decreased in CRC patients in CCCC and UACC CRC series. Circulating SMs are degraded primarily by S-SMase and serum S-SMase activity was significantly higher in UACC cases as compared to controls. Serum S-SMase activity was also measured in two series of adenoma patients to determine if S-SMase may serve as a biomarker for development of colorectal neoplasia. While S-SMase activity was significantly higher in adenoma patients compared to controls in the mostly white UACC series, S-SMase activity in samples from the Chicago Black series (CCCC) were indistinguishable from each other and significantly higher than UACC controls. Conclusions: Together, these studies suggest the potential for S-SMase activity to serve as a biomarker for colorectal neoplasia, with potential implications in some but perhaps not all populations.