Non-invasive metastasis prognosis from plasma metabolites in stage II colorectal cancer patients: The DACHS study
Inna Zaimenko
Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
Search for more papers by this authorCarsten Jaeger
Berlin Institute of Health, Berlin, Germany
Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum (MKFZ), Berlin, Germany
Search for more papers by this authorHermann Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorJenny Chang-Claude
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorMichael Hoffmeister
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorCarsten Grötzinger
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Search for more papers by this authorKatharina Detjen
Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Search for more papers by this authorSusen Burock
Charité Comprehensive Cancer Center, Berlin, Germany
Search for more papers by this authorClemens A. Schmitt
Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum (MKFZ), Berlin, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Ulrike Stein
Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Correspondence to: Jan Lisec, Bundesanstalt für Materialforschung und –prüfung (BAM), Richard-Willstätter-Straße 11, 12489 Berlin, Germany, Tel.: +49-30-8104-5891, E-mail: [email protected]; or Ulrike Stein, Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany, Tel.: 49-30-9406-3432, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Jan Lisec
Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum (MKFZ), Berlin, Germany
Division of Analytical Chemistry, Federal Institute for Materials Research and Testing (BAM), Berlin, Germany
Correspondence to: Jan Lisec, Bundesanstalt für Materialforschung und –prüfung (BAM), Richard-Willstätter-Straße 11, 12489 Berlin, Germany, Tel.: +49-30-8104-5891, E-mail: [email protected]; or Ulrike Stein, Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany, Tel.: 49-30-9406-3432, E-mail: [email protected]Search for more papers by this authorInna Zaimenko
Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
Search for more papers by this authorCarsten Jaeger
Berlin Institute of Health, Berlin, Germany
Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum (MKFZ), Berlin, Germany
Search for more papers by this authorHermann Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorJenny Chang-Claude
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorMichael Hoffmeister
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorCarsten Grötzinger
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Search for more papers by this authorKatharina Detjen
Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Search for more papers by this authorSusen Burock
Charité Comprehensive Cancer Center, Berlin, Germany
Search for more papers by this authorClemens A. Schmitt
Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum (MKFZ), Berlin, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Ulrike Stein
Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Correspondence to: Jan Lisec, Bundesanstalt für Materialforschung und –prüfung (BAM), Richard-Willstätter-Straße 11, 12489 Berlin, Germany, Tel.: +49-30-8104-5891, E-mail: [email protected]; or Ulrike Stein, Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany, Tel.: 49-30-9406-3432, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Jan Lisec
Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum (MKFZ), Berlin, Germany
Division of Analytical Chemistry, Federal Institute for Materials Research and Testing (BAM), Berlin, Germany
Correspondence to: Jan Lisec, Bundesanstalt für Materialforschung und –prüfung (BAM), Richard-Willstätter-Straße 11, 12489 Berlin, Germany, Tel.: +49-30-8104-5891, E-mail: [email protected]; or Ulrike Stein, Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany, Tel.: 49-30-9406-3432, E-mail: [email protected]Search for more papers by this authorAbstract
Metastasis is the main cause of death from colorectal cancer (CRC). About 20% of stage II CRC patients develop metastasis during the course of disease. We performed metabolic profiling of plasma samples from non-metastasized and metachronously metastasized stage II CRC patients to assess the potential of plasma metabolites to serve as biomarkers for stratification of stage II CRC patients according to metastasis risk. We compared the metabolic profiles of plasma samples prospectively obtained prior to metastasis formation from non-metastasized vs. metachronously metastasized stage II CRC patients of the German population-based case–control multicenter DACHS study retrospectively. Plasma samples were analyzed from stage II CRC patients for whom follow-up data including the information on metachronous metastasis were available. To identify metabolites distinguishing non-metastasized from metachronously metastasized stage II CRC patients robust supervised classifications using decision trees and support vector machines were performed and verified by 10-fold cross-validation, by nested cross-validation and by traditional validation using training and test sets. We found that metabolic profiles distinguish non-metastasized from metachronously metastasized stage II CRC patients. Classification models from decision trees and support vector machines with 10-fold cross-validation gave average accuracy of 0.75 (sensitivity 0.79, specificity 0.7) and 0.82 (sensitivity 0.85, specificity 0.77), respectively, correctly predicting metachronous metastasis in stage II CRC patients. Taken together, plasma metabolic profiles distinguished non-metastasized and metachronously metastasized stage II CRC patients. The classification models consisting of few metabolites stratify non-invasively stage II CRC patients according to their risk for metachronous metastasis.
Abstract
What's new?
Metastasis is the leading cause of death from colorectal cancer (CRC). New predictive biomarkers are urgently needed, as 25-50% of patients with stage I-III CRC will develop distant metastases after surgery. Here, the authors analyzed plasma from stage-II CRC patients prior to any metastasis, and asked whether plasma metabolites differed between those patients who later developed metastases and those who did not. The answer was ‘yes.’ The metabolic-profiling models developed in this study were able to correctly predict later metastases in up to 82% of patients.
Conflicts of interest
The authors declared no conflict of interests.
Supporting Information
| Filename | Description |
|---|---|
| ijc32076-sup-0001-TableS1.xlsxPDF document, 66.9 KB | Supporting Infoitem Table S1 |
| ijc32076-sup-0002-FigureS1.pptxPowerPoint 2007 presentation , 157.8 KB | Figure S1 A PCA on the complete data matrix (590 metabolites) after pareto normalization. Annotations in the plot indicate that no ANOVA based filtering was applied (p ≤ 1). While separation of patient groups is moderate, also no other inherent structure is visible within the first two components indicating no technical bias |
| ijc32076-sup-0003-FigureS2.pptxPowerPoint 2007 presentation , 74.4 KB | Figure S2 DT prediction with 100 random selections of 15 MET samples each and a fixed set of 50 NON samples analyzed each in 10-fold CV. This test is done to better resemble the actual population wide distribution of MET patients compared to NON (approximately ~25/75). For permuted data (lower panel) we observe on average the expected values for Sensitivity (NON group) and Specificity (MET group) resembling the population frequency (75% and 25% respectively). Both values are significantly higher for observed data (upper panel), leading to an overall accuracy of 0.78. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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