cancer metabolomics and its applications leo l. cheng massachusetts general hospital harvard medical...

Cancer Metabolomicsand Its Applications

Leo L. Cheng

Massachusetts General Hospital

Harvard Medical School

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Informatics for Cancer Diagnosis- Altered molecular biology

Ris

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Clinical Relevance

Genomics

Proteomics

Metabolo-mics

Pathology

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HRMAS MRS - Tissue Samples (~10mg)

- High Resolution Magic Angle Spinning

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w/o HRMAS

w/ HRMAS

x400

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HRMAS MRS

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HRMAS MRS

P1 P2 P3 P35 P36

S1 p1,1 p2,1 p3,1 p35,1 p36,1

S2 p1,2 p2,2 p3,2 p35,2 p36,2

S3 p1,3 p2,3 p3,3 p35,3 p36,3

S198 p1,198 p2,198 p3,198 p35,198 p36,198

S199 p1,199 p2,199 p3,199 p35,199 p36,199

PC1 PC2 PC3 PC35 PC36

P1 c1,1 c2,1 c3,1 c35,1 c36,1

P2 c1,2 c2,2 c3.2 c35,2 c36,2

P3 c1,3 c2,3 c3,3 c35,3 c36,3

P35 c1,35 c2,35 c3,35 c35,35 c36,35

P36 c1,36 c2,36 c3,36 c35,36 c36,36

Principal Component Analysis

- 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)

Peak Intensity

PC Coefficient

- 199 samples from 82 prostatectomy cases.

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Prostate Tissue

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E. V. % Cum%Epithelium

(r, p)

Cancer

(r, p)

Stroma

(r, p)

PC2 5.93 16.48 43.540.381,

<0.0001-0.303,

<0.0001

PC13 0.67 1.87 85.660.146, 0.0401

-0.154, 0.0302

PC14 0.55 1.54 87.20-0.160, 0.0243

-0.217, 0.0021

- First 16 PCs vs. Vol% of Epithelium, Cancer, & Stroma

Linear Regressions Analysis - Concentration

-20/199 samples have cancer glands; -13/82 cases have paired cancer/histol-benign analyzed;-12/13T2 and 1/13T3 tumors.

Canonical (Discriminant) Analysis- Metabolomic (concentration) Profile

10

Histo-benign

CancerP < 0.0001

0 1 2 3 4 5 6 7 8 9

Canonical Score 1

0

1

2

3

4

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6

Can

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core

2

9L. L. Cheng Cancer Res. 2005;65:3030-3034

Predicting Cancer Stage

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

MetabolomicImaging

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MRSI

Carhuapoma JR etal. Stroke 2000, 31:726-73212L. L. Cheng

MRSI

Horn JJ etal. Radiology 2006, 238:192-19913L. L. Cheng

Metabolomic Imaging - Phantom

14T

7T

1

3 2

14L. L. ChengSci. Transl. Med, 2010;2:16ra8

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VEigen %Cum

%PCa vs.

HBHB Epi PCa Epi Stroma

PC1 9.2 25.5 25.5 p<0.050 p<0.001

PC3 3.4 9.4 49.7 p<0.001

PC6 1.9 5.3 69.0 p<0.017 p<0.002 p<0.003

PC10 1.0 2.8 83.3 p<0.026

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

Linear Regressions Analysis – Relative Intensity

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Canonical (Discriminant) Analysis- Metabolomic (Relative Intensity) Profile

-12/13T2 and 1/13T3 tumors.

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

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-icj,i*pi,2 ; (i=1,2, … 36)

Metabolomic Profiles

Canonical Analysis (PCk, k=L,M … N):Canonical Score X for Sample 2 =

= BX-(eL,X*PCL+eM,X*PCM+…+eN,X*PCN) = BX-kek,X*PCk; (k=L,M … N) = BX-kek,X*(Ak-ick,i*pi,2) = BX-(kek,X*Ak)-ik ek,X*ck,i) pi,2

Overall Loading Factor

ek,X*ck,i

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Metabolomic Imaging - Whole Prostate ex vivo

Urethra

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• Five prostates from prostatectomies;Metabolomic Imaging

• 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)22L. L. Cheng

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

Metabolomic Imaging

T2

T3

R2 = 0.998P < 0.001

P < 0.004 (T2)P < 0.008 (all)

AUC = 0.969(T2 Only)AUC = 0.925(Including T3)

R2 = 0.975P < 0.013

T2

T3

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Predicting TumorRecurrence

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Chemical Recurrence

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

1 - Specificity

PC4, 6, 7, & 8 PC1-9

Chemical Recurrence

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AUC = 0.71 AUC = 0.78

Prostate, 2009, doi:10.1002/pros.21103

Lung CancerSerum Profiles

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Lung Cancer

Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.01228L. L. Cheng

Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.01229L. L. Cheng

Lung Cancer: Clinical Data

Lung Cancer: Canonical Analysis

Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.01230L. L. Cheng

Lung Cancer: Nominal Logistic Regression Analysis

Serum Profile Based on Tissue (SPT)

AC:-1.10+0.27SPT-1.27SP

SCC:-1.73-1.86SPT+0.77SP

Ctrl:-2.90+2.12SPT+1.21SP

Nominal Logisticp < 0.0001

Lung Cancer, 2009, doi:10.1016/j.lingcan.2009.05.01231L. L. Cheng

L. L. Cheng 32

MGH/HMSMelissa A. BurnsJennifer L. TaylorWnelei He Elkan F. HalpernW. Scott McDougalChin-Lee Wu

MGH/HMSChin-Lee WuKate W. JordanEva M. RataiChristen B. Adkins Elita M. DeFeoBruce G. JenkinsW. Scott McDougal

U. Wis-MilwaukeeJinhua Sheng Leslie Ying

MGH/HMSChristen B. Adkins Yifen ZhangElkan F. HalpernW. Scott McDougalChin-Lee Wu

Charite U., BerlinAndreas MaxeinerMatthias Taupitz

MGH/HMSKate W. JordanChristen B. Adkins Eugene J. Mark

HSPH/MGH/HMSLi SuDavid C. Christiani

Cancer Res 2005 Sci Transl Med 2010 Lung Ca 2009Prostate 2009

Conclusions and Acknowledgements

Grant Supports: NCI/NIH, DOD, MGH Martinos Center, and Bertucci Prostate Cancer Research Fund