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The desmoid tumor proteome: identifying molecular markers using a clinically annotated tissue microarray. Shohrae Hajibashi, Wei-Lien Wang, Alexander J.F. Lazar, Daniel Tuvin, Carla L. Warneke, Dolores Lopez-Terrada, Raphael E. Pollock, Dina Lev. Sarcoma Research Laboratory Houston, TX.

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The desmoid tumor proteome: identifying molecular markers using a clinically annotated tissue microarray

Shohrae Hajibashi, Wei-Lien Wang, Alexander J.F. Lazar, Daniel Tuvin, Carla L. Warneke, Dolores Lopez-Terrada, Raphael E. Pollock, Dina Lev

Sarcoma Research Laboratory

Houston, TX


Unresolved clinical issues
Unresolved clinical issues using a clinically annotated tissue microarray

  • Lack of prognostic markers

  • Need for better therapeutics


Bridging the biological gap
Bridging the biological gap using a clinically annotated tissue microarray

  • Impediments to progress:

    • Relative rarity

    • Limited collected human specimens

    • No cell lines

    • No animal models

  • Molecular determinants not well understood


UTMDACC desmoid tissue microarray (TMA) using a clinically annotated tissue microarray

  • Formalin-fixed, paraffin-embedded desmoid tumors (195 specimens from 160 patients; 1985-2005)

  • Clinical information including:

    • Demographic

    • Therapeutic

    • Clinical outcome


UTMDACC desmoid TMA using a clinically annotated tissue microarray

  • Automated TMA apparatus: 0.6-mm punch samples (2/case) formatted into three recipient blocks

  • 195 specimens: 110 primary/ 85 recurrent; 27 autologous pairs; 18 scars

  • H&E-staining of 4-µm TMA sections used to verify all samples


Clinical annotation using a clinically annotated tissue microarray

  • Gender: F 62%; M 38%

  • Median age: 32 yr old

  • Site

    • Superficial trunk 39%

    • Extremity 38%

    • Deep trunk/mesentery 13%

    • Head and neck 10%

  • Median size: 6 cm

  • FAP associated: 8%


Desmoid TMA: useful for identifying over-expressed proteins using a clinically annotated tissue microarray


Example: high -catenin TMA nuclear expression correlates with outcome

High, n=49

Low-moderate, n=40

p=0.0406

TMA: ~98% of the desmoids showed nuclear reactivity


Specific mutations in the with outcome-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors

Am J Path. 173(5):1518-27; Nov 2008

47 (53%)

20 (22%)

15 (17%)

p=0.0002


Next steps an algorithm for desmoid investigation
Next steps…an algorithm for desmoid investigation with outcome

1. “Up front” identification of potential desmoid-related/specific over-expressed genes

2. Confirm that gene over-expression leads to protein over production (TMA; different samples)

3. Validate these proteins as prognostic markers

4. Examine as possible targets for therapy


1 up front identification of potential desmoid related specific over expressed genes
1. “Up front” identification of potential desmoid-related/specific over-expressed genes

Human exonic evidence based oligonucleotide (HEEBOChip) microarray

10 desmoid tumor samples (20 additional specimens;

van de Rijn/West; Stanford)


1 up front identification of potential desmoid related specific over expressed genes1
1. “Up front” identification of potential desmoid-related/specific over-expressed genes


2. Confirm that gene over-expression leads to protein over production (TMA)

ADAM12

MDK

Scar

Desmoid

Scar

Desmoid

100% (+)

43% (+)


3 4 examine adam12 as a prognostic marker possible target for future desmoid therapy
3 & 4. Examine ADAM12 as a prognostic marker; possible target for (future) desmoid therapy?

ADAM12 protein: disintegrin

and metalloprotease; up-regulated in many human cancers

Role in tumor progression

ECM remodeling

resistance to apoptosis

prognostic marker:

breast/prostate cancers


3 4 examine adam12 as a prognostic marker possible target for future desmoid therapy1

ADAM12 target for (future) desmoid therapy?

Actin

3 & 4. Examine ADAM12 as a prognostic marker; possible target for (future) desmoid therapy?

ADAM12 over-expressed in desmoid cell cultures

NHF

Des 12

Des 2

Des 15

Anti-ADAM12 agents in pipe line…


Conclusions and implications
Conclusions and implications: target for (future) desmoid therapy?

  • Needed: comprehensive strategies to identify desmoid-related prognostic markers and therapeutic targets

  • High throughput gene/protein expression arrays for target identification: a potential approach

  • TMA studies: intense nuclear -catenin expression associates with less aggressive desmoid behavior

  • ADAM12: highly expressed in desmoids; currently being studied as a prognostic factor and therapeutic target


Acknowledgements
Acknowledgements target for (future) desmoid therapy?

  • The Sarcoma Research Laboratory

    • D. Lev, MD

    • R. Pollock, MD/PhD

    • A. Lazar, MD/PhD

    • Colleagues and staff

  • Stanford University Medical Center

    • M. van de Rijn, MD/PhD

    • R. West, MD/PhD

  • Desmoid Tumor Research Foundation


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