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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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Cancer metabolomics and its applications

Cancer Metabolomics

and Its Applications

Leo L. Cheng

Massachusetts General Hospital

Harvard Medical School

L. L. Cheng


Cancer metabolomics and its applications

Informatics for Cancer Diagnosis

- Altered molecular biology

Genomics

Risk Predictability

Proteomics

Metabolo-

mics

Pathology

Clinical Relevance

L. L. Cheng


Cancer metabolomics and its applications

HRMAS MRS - Tissue Samples (~10mg)

- High Resolution Magic Angle Spinning

L. L. Cheng


Cancer metabolomics and its applications

w/o HRMAS

w/ HRMAS

HRMAS MRS

x400

L. L. Cheng


Cancer metabolomics and its applications

HRMAS MRS

L. L. Cheng


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

Prostate Tissue

L. L. Cheng


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

Predicting Cancer Stage

L. L. Cheng

Cancer Res. 2005;65:3030-3034


Cancer metabolomics and its applications

Metabolomic

Imaging

L. L. Cheng


Cancer metabolomics and its applications

MRSI

Carhuapoma JR etal. Stroke 2000, 31:726-732

L. L. Cheng


Cancer metabolomics and its applications

MRSI

Horn JJ etal. Radiology 2006, 238:192-199

L. L. Cheng


Cancer metabolomics and its applications

1

2

3

Metabolomic Imaging - Phantom

7T

14T

L. L. Cheng

Sci. Transl. Med, 2010;2:16ra8


Cancer metabolomics and its applications

Linear Regressions Analysis – Relative Intensity

- First 10 PCs vs. Vol% of Epithelium, Cancer, & Stroma

L. L. Cheng


Cancer metabolomics and its applications

Canonical (Discriminant) Analysis

- Metabolomic (Relative Intensity) Profile

  • 12/13T2 and 1/13T3 tumors.

L. L. Cheng

Sci. Transl. Med, 2010;2:16ra8


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

L. L. Cheng


Cancer metabolomics and its applications

L. L. Cheng


Cancer metabolomics and its applications

L. L. Cheng


Cancer metabolomics and its applications

Metabolomic Imaging - Whole Prostate ex vivo

Urethra

L. L. Cheng

Sci. Transl. Med, 2010;2:16ra8


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

Predicting Tumor

Recurrence

L. L. Cheng


Cancer metabolomics and its applications

Chemical Recurrence

L. L. Cheng

Prostate, 2009, doi:10.1002/pros.21103


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

Lung Cancer

Serum Profiles

L. L. Cheng


Cancer metabolomics and its applications

Lung Cancer

L. L. Cheng

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


Cancer metabolomics and its applications

Lung Cancer: Clinical Data

L. L. Cheng

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


Cancer metabolomics and its applications

Lung Cancer: Canonical Analysis

L. L. Cheng

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


Cancer metabolomics and its applications

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


Cancer metabolomics and its applications

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


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