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Cancer Metabolomics and Its Applications. Leo L. Cheng Massachusetts General Hospital Harvard Medical School. Informatics for Cancer Diagnosis - Altered molecular biology. Genomics. Risk Predictability. Proteomics. Metabolo- mics. Pathology. Clinical Relevance.

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Cancer Metabolomics and Its Applications


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    1. Cancer Metabolomics and Its Applications Leo L. Cheng Massachusetts General Hospital Harvard Medical School L. L. Cheng

    2. Informatics for Cancer Diagnosis - Altered molecular biology Genomics Risk Predictability Proteomics Metabolo- mics Pathology Clinical Relevance L. L. Cheng

    3. HRMAS MRS - Tissue Samples (~10mg) - High Resolution Magic Angle Spinning L. L. Cheng

    4. w/o HRMAS w/ HRMAS HRMAS MRS x400 L. L. Cheng

    5. HRMAS MRS L. L. Cheng

    6. Peak Intensity PC Coefficient Principal Component Analysis - 199 samples from 82 prostatectomy cases. - Intensities of 36 most common and intensive peaks. Example: PC3 for Sample 2 = A-(c3,1*p1,2 +c3,2*p2,2 +c3,3*p3,2+ … +c3,36*p36,2) L. L. Cheng

    7. Prostate Tissue L. L. Cheng

    8. Linear Regressions Analysis - Concentration - First 16 PCs vs. Vol% of Epithelium, Cancer, & Stroma • 20/199 samples have cancer glands; • 13/82 cases have paired cancer/histol-benign analyzed; • 12/13T2 and 1/13T3 tumors. L. L. Cheng

    9. Canonical (Discriminant) Analysis - Metabolomic (concentration) Profile 6 Cancer P < 0.0001 5 4 Canonical Score 2 3 2 1 Histo-benign 0 0 1 2 3 4 5 6 7 8 9 10 Canonical Score 1 L. L. Cheng Cancer Res. 2005;65:3030-3034

    10. Predicting Cancer Stage L. L. Cheng Cancer Res. 2005;65:3030-3034

    11. Metabolomic Imaging L. L. Cheng

    12. MRSI Carhuapoma JR etal. Stroke 2000, 31:726-732 L. L. Cheng

    13. MRSI Horn JJ etal. Radiology 2006, 238:192-199 L. L. Cheng

    14. 1 2 3 Metabolomic Imaging - Phantom 7T 14T L. L. Cheng Sci. Transl. Med, 2010;2:16ra8

    15. Linear Regressions Analysis – Relative Intensity - First 10 PCs vs. Vol% of Epithelium, Cancer, & Stroma L. L. Cheng

    16. Canonical (Discriminant) Analysis - Metabolomic (Relative Intensity) Profile • 12/13T2 and 1/13T3 tumors. L. L. Cheng Sci. Transl. Med, 2010;2:16ra8

    17. Metabolomic Profiles Principal Component Analysis (Std Peak pi, i=1,2, … 36): PCj for Sample 2 = Aj-(cj,1*p1,2+cj,2*p2,2+cj,3*p3,2+…+cj,36*p36,2) = Aj-Sicj,i*pi,2 ; (i=1,2, … 36) Canonical Analysis (PCk, k=L,M … N): Canonical Score X for Sample 2 = = BX-(eL,X*PCL+eM,X*PCM+…+eN,X*PCN) = BX-Skek,X*PCk; (k=L,M … N) = BX-Skek,X*(Ak-Sick,i*pi,2) = BX-(Skek,X*Ak)-Si (Sk ek,X*ck,i) pi,2 ek,X*ck,i Overall Loading Factor L. L. Cheng

    18. L. L. Cheng

    19. L. L. Cheng

    20. L. L. Cheng

    21. Metabolomic Imaging - Whole Prostate ex vivo Urethra L. L. Cheng Sci. Transl. Med, 2010;2:16ra8

    22. Metabolomic Imaging • Five prostates from prostatectomies; • 7T human scanner; • Three planes of 2D localized MRS, 16x16; • Voxel = 3x3x3 mm3; • Seven tumor histology regions, five inside - four T2 and one T3; • Seven planes analyzed; • Thirteen metabolomic regions (>M+SD, >2) L. L. Cheng Sci. Transl. Med, 2010;2:16ra8

    23. R2 = 0.975 P < 0.013 R2 = 0.998 P < 0.001 T2 T2 T3 T3 P < 0.004 (T2) P < 0.008 (all) AUC = 0.969 (T2 Only) AUC = 0.925 (Including T3) Metabolomic Imaging L. L. Cheng Sci. Transl. Med, 2010;2:16ra8

    24. Predicting Tumor Recurrence L. L. Cheng

    25. Chemical Recurrence L. L. Cheng Prostate, 2009, doi:10.1002/pros.21103

    26. Chemical Recurrence PC4, 6, 7, & 8 PC1-9 Sensitivity AUC = 0.71 AUC = 0.78 1 - Specificity L. L. Cheng Prostate, 2009, doi:10.1002/pros.21103

    27. Lung Cancer Serum Profiles L. L. Cheng

    28. Lung Cancer L. L. Cheng Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.012

    29. Lung Cancer: Clinical Data L. L. Cheng Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.012

    30. Lung Cancer: Canonical Analysis L. L. Cheng Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.012

    31. Lung Cancer: Nominal Logistic Regression Analysis Serum Profile from Serum Alone (SP) Nominal Logistic p < 0.0001 Ctrl: -2.90+2.12SPT+1.21SP SCC: -1.73-1.86SPT+0.77SP AC: -1.10+0.27SPT-1.27SP Serum Profile Based on Tissue (SPT) L. L. Cheng Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.012

    32. Conclusions and Acknowledgements Cancer Res 2005 Sci Transl Med 2010 Prostate 2009 Lung Ca 2009 MGH/HMS Melissa A. Burns Jennifer L. Taylor Wnelei He Elkan F. Halpern W. Scott McDougal Chin-Lee Wu MGH/HMS Christen B. Adkins Yifen Zhang Elkan F. Halpern W. Scott McDougal Chin-Lee Wu Charite U., Berlin Andreas Maxeiner Matthias Taupitz MGH/HMS Kate W. Jordan Christen B. Adkins Eugene J. Mark HSPH/MGH/HMS Li Su David C. Christiani MGH/HMS Chin-Lee Wu Kate W. Jordan Eva M. Ratai Christen B. Adkins Elita M. DeFeo Bruce G. Jenkins W. Scott McDougal U. Wis-Milwaukee Jinhua Sheng Leslie Ying L. L. Cheng Grant Supports: NCI/NIH, DOD, MGH Martinos Center, and Bertucci Prostate Cancer Research Fund