Alveolar Soft Part Sarcoma (ASPS) Has a Unique Angiogenic Profile and Relatively Favorable Clinical Outcome

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Alveolar Soft Part Sarcoma (ASPS) Has a Unique
Angiogenic Profile and Relatively Favorable
Clinical Outcome

• Alexander Lazar1,  Das  Parimal1, 
  Daniel  Tuvin1,
• Quan-Sheng Zhu1, Borys  Korchin1, 
• Dolores  Lopez-Terrada2,  Raphael E. Pollock1, 
• Dina  Lev1
• 1Sarcoma Research Center, The University of Texas
  MD Anderson Cancer Center, Houston, Texas, United
  States  2Texas Childrens Hospital / Baylor
  Medical School, Houston, Texas, United States

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Sarcoma ClassificationBased on
Histiogenesis/Line of Differentiation
Osteosarcoma
MFH
Chondrosarcoma
Leiomyosarcoma
Rhabdomyosarcoma
Angiosarcoma
Liposarcoma
MPNST
Synovial Sarcoma - ??
Ewings Sarcoma/PNET - ??
Alveolar Soft Part Sarcoma - ??
Courtesy of Dr. Brian Rubin, Cleveland Clinic
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Alveolar Soft Part Sarcoma

• Christopherson, Foote, Stewart 1952
• Smetana Scott 1951
• Rare
• Relatively indolent, but metastatic
• Unknown histiogenesis
• Characteristic translocation

Folpe Deyrup, J Clin Pathol, 2006
59(11)1127-32.
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ASPS

• der(17) t(X17)(p11.2q25), ASPSCR1/ASPL-TFE3
• Highly angiogenic
• ? Prevalence of the translocation?
• ? Molecular events underlying angiogenesis

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UTMDACC ASPS Cohort

• 71 patients (1986-2005)
• 43 (61) male 28 (39) female
• Median F/U (initial Dx) 8 years
• 3 fresh frozen tumors
• 33 FFPE tumor tissue
• 17 primary 16 metastatic
• TMA
• 15 with extractable RNA

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• Long term survival despite metastatic disease.
• Odd metastatic pattern
• Brain
• Bone
• Lung, etc.

Lazar et al. Clin Cancer Res, 2007, in press.
U. Utah, CTOS 2007, poster 828.
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monocarboxylate transporter 1 CD147
Ladanyi et al. Am J Pathol, 2002 160(4)1215-21.
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ASPS Fusion Event

• TFE3 (Xp11)
• Transcription Factor
• bHLH MiTF, TFEB and TFEC
• N-terminal activation domain
• ASPSCR1/ASPL (17p25)
• Function unknown
• ? Transcription activation

Ladanyi et al. Oncogene, 2001 20(1)48-57.
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• ASPS
• Unbalanced
• G2 phase, cell cycle
• Type 1 AD-
• Type 2 AD
• Pediatric RCC TFE3
• Balanced
• ASPSCR1 / ASPL
• NonO
• PSF
• PPRC
• CLTC
• Alpha-TFEB

Huang et al. Genes Chromos Cancer, 2005
44(2)170-6.
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• Molecular testing
• RT-PCR
• Type 1
• Type 2
• FISH
• TFE3 (Xp11)
• ASPL / ASPSCR1
• (17q25)

Aulmann et al. Histopathol, 2007 50(7)881-6.
Ladanyi et al. Oncogene, 2001 20(1)48-57.
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Sex Age RNA (ng/µl) PCR b-Actin PCR Fusion Fusion Type
1 M 48 N/A Positive Positive Type 1
2 F 27 1011 Pos/Pos Neg/Neg None
3 M 24 933 Positive Weak Type 2
4 M 31 1785 Positive Positive Type 1
5 F 27 2634 Positive Positive Type 1
6 F 4 117 Positive Weak Type 1
7 F 32 2062 Positive Positive Type 1
8 F 31 N/A Positive Positive Type 2
9 F 20 1209 Pos/Pos Neg/Neg None
10 M 42 1296 Positive Positive Type 1
11 F 25 668 Positive Positive Type 2
12 M 36 933 Pos/Pos Neg/Pos Type 2
13 M 40 521 Positive Positive Type 2
14 M 20 125 Positive Positive Type 2
15 M 51 3171 Positive Positive Type 1

• 33 samples
• 15 RNA
• 13 of 15
• 7 Type 1
• 6 Type 2
• 1 recipr. (T2)
• No differences

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Argani et al. Am J Surg Pathol, 2003
27(6)750-61.
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Angiogenic Analysis

• 3 frozen cases (T N)
• Oligo GEArray Human Angiogenesis Microarray
  (OHS-024 SuperArray Bioscience Corporation
  Frederick, MD)
• 113 angiogenesis-related genes
• Threshold 1.5-fold

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No VEGFs, FGFs, PDGFs, angiopoietins, or matrix
metaloproteases

• Angiogenin
• MDK
• HIF1A
• TGFB1
• JAG1

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Jag-1

• 32 Mod to High
• 1 Low

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Angiogenin

• 29 Mod to High
• 4 Low

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Midkine

• 26 Mod to High
• 7 Low

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TFE Response Elements

• In silico (4 Kb of promoter)
• E-box consensus sequence (CAC/TGTG)
• TGFb 3
• MDK 1
• ANGIOGENIN 2
• JAG1 1
• HIF1a 1

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Conclusions

• Metastatic, relatively indolent
• Fusion event is characteristic
• Angiogenic profile is unusual
• No VEGFs, FGFs, PDGFs, angiopoietins, or matrix
  metaloproteases
• Profile not seen in other sarcomas
• ? Treatment targets

Ladanyi et al. Oncogene, 2001 20(1)48-57.
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Acknowledgments

• UTMDACC Sarcoma Research Center
• Raphael Pollock, Director (Surgical Oncology)
• Dina Lev, PI Sarcoma Research Lab (Cancer
  Biology)
• Daniel  Tuvin
• Quan-Sheng Zhu
• Borys  Korchin
• Peter Pisters (Surgical Oncology)
• Baylor College of Medicine
• Dolores  Lopez-Terrada (Pathology)
• UTMDACC Physician Scientist Program
• Sarcoma Patients

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Tsuda et al. Cancer Res, 2007 67(3)919-929.
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Survival in ASPS is related to time to metastasis
and tumor size (71 patients at single institution)
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