Tumor Tissue-Specific Biomarkers of Colorectal Cancer by Anatomic Location and Stage

Authors

Yuping Cai, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.Follow
Nicholas J. Rattray, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.Follow
Qian Zhang, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.Follow
Varvara Mironova, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.Follow
Alvaro Santos-Neto, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.Follow
Engjel Muca, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.Follow
Ana K. Vollmar, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.
Kuo-Shun Hsu, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Zahra Rattray, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.Follow
Justin R. Cross, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.Follow
Yawei Zhang, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.Follow
Philip B. Paty, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.Follow
Sajid A. Khan, Department of Surgery, Division of Surgical Oncology, Yale University School of Medicine, New Haven, CT 06520, USA.Follow
Caroline H. Johnson, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.Follow

Document Type

Article

Publication Title

Metabolites

Abstract

The progress in the discovery and validation of metabolite biomarkers for the detection of colorectal cancer (CRC) has been hampered by the lack of reproducibility between study cohorts. The majority of discovery-phase biomarker studies have used patient blood samples to identify disease-related metabolites, but this pre-validation phase is confounded by non-specific disease influences on the metabolome. We therefore propose that metabolite biomarker discovery would have greater success and higher reproducibility for CRC if the discovery phase was conducted in tumor tissues, to find metabolites that have higher specificity to the metabolic consequences of the disease, that are then validated in blood samples. This would thereby eliminate any non-tumor and/or body response effects to the disease. In this study, we performed comprehensive untargeted metabolomics analyses on normal (adjacent) colon and tumor tissues from CRC patients, revealing tumor tissue-specific biomarkers (n = 39/group). We identified 28 highly discriminatory tumor tissue metabolite biomarkers of CRC by orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate analyses (VIP > 1.5, p < 0.05). A stepwise selection procedure was used to identify nine metabolites that were the most predictive of CRC with areas under the curve (AUCs) of >0.96, using various models. We further identified five biomarkers that were specific to the anatomic location of tumors in the colon (n = 236). The combination of these five metabolites (S-adenosyl-L-homocysteine, formylmethionine, fucose 1-phosphate, lactate, and phenylalanine) demonstrated high differentiative capability for left- and right-sided colon cancers at stage I by internal cross-validation (AUC = 0.804, 95% confidence interval, CI 0.670-0.940). This study thus revealed nine discriminatory biomarkers of CRC that are now poised for external validation in a future independent cohort of samples. We also discovered a discrete metabolic signature to determine the anatomic location of the tumor at the earliest stage, thus potentially providing clinicians a means to identify individuals that could be triaged for additional screening regimens.

DOI

10.3390/metabo10060257

Publication Date

6-19-2020

Recommended Citation

Cai, Yuping; Rattray, Nicholas J.; Zhang, Qian; Mironova, Varvara; Santos-Neto, Alvaro; Muca, Engjel; Vollmar, Ana K.; Hsu, Kuo-Shun; Rattray, Zahra; Cross, Justin R.; Zhang, Yawei; Paty, Philip B.; Khan, Sajid A.; and Johnson, Caroline H., "Tumor Tissue-Specific Biomarkers of Colorectal Cancer by Anatomic Location and Stage" (2020). Surgery. 243.
https://scholar.bridgeporthospital.org/surgery/243

Identifier

32575361 (pubmed); PMC7345993 (pmc); 10.3390/metabo10060257 (doi); metabo10060257 (pii)