CEACAM6 is upregulated by Helicobacter pylori CagA and is a biomarker for early gastric cancer

// Rony K. Roy 1, * , Michal M. Hoppe 1, * , Supriya Srivastava 1 , Animesh Samanta 2 , Neel Sharma 3 , Kar Tong Tan 1 , Henry Yang 1 , Dominic C. Voon 1 , Brendan Pang 4 , Ming Teh 4 , Naoko Murata-Kamiya 5 , Masanori Hatakeyama 5 , Young-Tae Chang 2 , Wei Peng Yong 1, 6 , Yoshiaki Ito 1, 6 , Khek Yu Ho 2, 6 , Patrick Tan 1, 6 , Richie Soong 1 , Phillip H. Koeffler 1, 2 , Khay Guan Yeoh 2, 6 , Anand D. Jeyasekharan 1, 6 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 2 Department of Chemistry, National University of Singapore, Singapore 3 Division of Gastroenterology and Hepatology, National University Hospital, Singapore 4 Department of Pathology, National University Hospital, Singapore 5 University of Tokyo, Tokyo, Japan 6 Singapore Gastric Cancer Consortium, National University of Singapore, Singapore * These authors have contributed equally to this work Correspondence to: Khay Guan Yeoh, email: mdcykg@nus.edu.sg Anand D. Jeyasekharan, email: csiadj@nus.edu.sg Keywords: gastric cancer, biomarker, Helicobacter pylori, CEACAM6, endoscopy Received: February 19, 2016      Accepted: May 23, 2016      Published: July 11, 2016 ABSTRACT Early detection of gastric cancers saves lives, but remains a diagnostic challenge. In this study, we aimed to identify cell-surface biomarkers of early gastric cancer. We hypothesized that a subset of plasma membrane proteins induced by the Helicobacter pylori oncoprotein CagA will be retained in early gastric cancers through non-oncogene addiction. An inducible system for expression of CagA was used to identify differentially upregulated membrane protein transcripts in vitro . The top hits were then analyzed in gene expression datasets comparing transcriptome of gastric cancer with normal tissue, to focus on markers retained in cancer. Among the transcripts enriched upon CagA induction in vitro , a significant elevation of CEACAM6 was noted in gene expression datasets of gastric cancer. We used quantitative digital immunohistochemistry to measure CEACAM6 protein levels in tissue microarrays of gastric cancer. We demonstrate an increase in CEACAM6 in early gastric cancers, when compared to matched normal tissue, with an AUC of 0.83 for diagnostic validity. Finally, we show that a fluorescently conjugated CEACAM6 antibody binds avidly to freshly resected gastric cancer xenograft samples and can be detected by endoscopy in real time. Together, these results suggest that CEACAM6 upregulation is a cell surface response to H. pylori CagA, and is retained in early gastric cancers. They highlight a novel link between CEACAM6 expression and CagA in gastric cancer, and suggest CEACAM6 to be a promising biomarker to aid with the fluorescent endoscopic diagnosis of early neoplastic lesions in the stomach.