Distinct Performance of Methylated SEPT9 in Upper and Lower Gastrointestinal Cancers and Combined Detection with Protein Markers

Background: The performance of methylated SEPT9 (mSEPT9) in lower gastrointestinal (GI) cancer (colorectal cancer) has been extensively investigated; however, its performance in upper GI cancer (esophageal cancer and gastric cancer) and the comparison with lower GI cancer have rarely been studied. Methods: A total of 1854 subjects, including 344 upper GI cancer patients, 459 lower GI cancer patients, and 1051 noncancer subjects, were recruited in this prospective cohort study. A modified single polymerase chain reaction test for detecting mSEPT9 was used for plasma detection. Results: The sensitivity of mSEPT9 for upper and lower GI cancers was 45.3% and 74.8%, and the corresponding specificities were 85.6% and 86.5%, with areas under curve (AUC) of 0.71 and 0.80, respectively. mSEPT9 exhibited lower sensitivity in stage I than stage II-IV cancer, while no difference in sensitivity was observed for different locations in upper or lower GI cancer. No difference in sensitivity was found among gross classifications, pathological classifications, and differentiation in upper GI cancer, but a higher sensitivity in infiltrative cancer and moderate and poorly differentiated cancers was observed in the lower GI. No difference in sensitivity was found between male and female in both cancers, while sensitivity increased with age for both cancers. Cancer antigen 724 (CA724) showed the highest sensitivity for upper GI cancers, and carcinoembryonic antigen (CEA) showed the highest sensitivity for lower GI cancers. The combination of CA724 with mSEPT9 increased the sensitivity to 67.5% in upper GI cancers, and the combination of mSEPT9 with CEA increased the sensitivity to 85.4% in lower GI cancers, with an AUC of 0.90 and 0.95, respectively. Conclusions:mSEPT9 exhibited a higher sensitivity in lower GI cancers than upper GI cancers. The combination of mSEPT9 with protein markers significantly enhanced the detection sensitivity in both cancers.