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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

Leo L. Cheng

Massachusetts General Hospital

Harvard Medical School

L. L. Cheng


Informatics for Cancer Diagnosis

- Altered molecular biology

Genomics

Risk Predictability

Proteomics

Metabolo-

mics

Pathology

Clinical Relevance

L. L. Cheng


HRMAS MRS - Tissue Samples (~10mg)

- High Resolution Magic Angle Spinning

L. L. Cheng


w/o HRMAS

w/ HRMAS

HRMAS MRS

x400

L. L. Cheng


HRMAS MRS

L. L. Cheng


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


Prostate Tissue

L. L. Cheng


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


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


Predicting Cancer Stage

L. L. Cheng

Cancer Res. 2005;65:3030-3034


Metabolomic

Imaging

L. L. Cheng


MRSI

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

L. L. Cheng


MRSI

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

L. L. Cheng


1

2

3

Metabolomic Imaging - Phantom

7T

14T

L. L. Cheng

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


Linear Regressions Analysis – Relative Intensity

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

L. L. Cheng


Canonical (Discriminant) Analysis

- Metabolomic (Relative Intensity) Profile

  • 12/13T2 and 1/13T3 tumors.

L. L. Cheng

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


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





Metabolomic Imaging - Whole Prostate ex vivo

Urethra

L. L. Cheng

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


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


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


Predicting Tumor

Recurrence

L. L. Cheng


Chemical Recurrence

L. L. Cheng

Prostate, 2009, doi:10.1002/pros.21103


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


Lung Cancer

Serum Profiles

L. L. Cheng


Lung Cancer

L. L. Cheng

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


Lung Cancer: Clinical Data

L. L. Cheng

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


Lung Cancer: Canonical Analysis

L. L. Cheng

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


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


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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