title: 1H HR-MAS NMR spectroscopy of tumor-induced local metabolic "field-effects" enables colorectal cancer staging and prognostication.
abstract: Colorectal cancer (CRC) is a major cause of morbidity and mortality in developed countries. Despite operative advances and the widespread adoption of combined-modality treatment, the 5-year survival rarely exceeds 60%. Improving our understanding of the biological processes involved in CRC development and progression will help generate new diagnostic and prognostic approaches. Previous studies have identified altered metabolism as a common feature in carcinogenesis, and quantitative measurement of this altered activity (metabonomics/metabolomics) has the potential to generate novel metabolite-based biomarkers for CRC diagnosis, staging and prognostication. In the present study we applied high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy to analyze metabolites in intact tumor samples (n = 83) and samples of adjacent mucosa (n = 87) obtained from 26 patients undergoing surgical resection for CRC. Orthogonal partial least-squares discriminant analysis (OPLS-DA) of metabolic profiles identified marked biochemical differences between cancer tissue and adjacent mucosa (R(2) = 0.72; Q(2) = 0.45; AUC = 0.91). Taurine, isoglutamine, choline, lactate, phenylalanine, tyrosine (increased concentrations in tumor tissue) together with lipids and triglycerides (decreased concentrations in tumor tissue) were the most discriminant metabolites between the two groups in the model. In addition, tumor tissue metabolic profiles were able to distinguish between tumors of different T- and N-stages according to TNM classification. Moreover, we found that tumor-adjacent mucosa (10 cm from the tumor margin) harbors unique metabolic field changes that distinguish tumors according to T- and N-stage with higher predictive capability than tumor tissue itself and are accurately predictive of 5-year survival (AUC = 0.88), offering a highly novel means of tumor classification and prognostication in CRC.
authors.affiliation: Section of Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, SW7 2AZ London, United Kingdom.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Jiménez
authors.forename: Reza
authors.initials: R
authors.lastname: Mirnezami
authors.forename: James
authors.initials: J
authors.lastname: Kinross
authors.forename: Olivier
authors.initials: O
authors.lastname: Cloarec
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldin
authors.forename: Paul
authors.initials: P
authors.lastname: Ziprin
authors.forename: Ara
authors.initials: A
authors.lastname: Darzi
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000596:Amino Acids / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D002794:Choline / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D009367:Neoplasm Staging / Q000379:methods; D011237:Predictive Value of Tests; D016019:Survival Analysis; D014280:Triglycerides / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D000596:Amino Acids; D014408:Biomarkers, Tumor; D014280:Triglycerides; D019344:Lactic Acid; D002794:Choline