Molecular analysis of sporadic and neurofibromatosis 1 (NF1)-associated malignant peripheral nerve sheath tumors

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Molecular analysis of sporadic and
neurofibromatosis 1 (NF1)-associated malignant
peripheral nerve sheath tumors
Mark A. Watson, Arie Perry, and David H.
Gutmann Washington University School of
Medicine Supported by funding from the
Department of Defense and Washington
University/Siteman Cancer Center
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• MPNST
• Devastating tumor
• Poor response to therapy
• Poor patient survival
• Patients with neurofibromatosis 1 (NF1) harbor
  10 lifetime risk of developing MPNST

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• NF1 loss seen in 76 MPNST by FISH
• Neurofibromin loss seen in 9/9 MPNST

NF1 inactivation is critical event in MPNST
pathogenesis
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p16 deletion in MPNSTs
Tumor p16 deletion p16 HD Schwannoma
0/5 0/5 Plexiform neurofibroma
0/13 0/13 MPNST 16/20 9/20
(75) (45) Synovial sarcoma 5/7
0/7 (71) Fibrosarcoma 5/6
0/6 (83) Hemangiopericytoma
8/12 0/12 (67)
CEP9 p16
J. Neuropath Exp. Neurol., 2002
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EGFR amplification in MPNSTs
CEP7 EGFR
Tumor EGF-R amplification Schwannoma
0/5 Plexiform neurofibroma
0/13 MPNST 5/19
(26) Synovial sarcoma 0/7
Fibrosarcoma 0/6
Hemangiopericytoma 0/13
J. Neuropath Exp. Neurol., 2002
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Gene expression profiling 25 NF1-associated 17
sporadic tumors
Genetic signature to distinguish NF1-associated
from sporadic? Genetic signature to predict
clinical behavior?
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4247 4263 4260 4236 4252 4261424042744262425742414
258 4238 4239 4276 42704235 4244 4266 426942514230
42644271 4232 4242 4245 42314255423442534233425442
3742564265424342594246425042484275424942684267
SIAT9 MGLL GCM1 SGCE SEC14L1 DDX21
SSSSSSSSSsnssSsnsnNnnnNnnnsNNnsNsnnNNnnnNNnNn
Few, if any, gene expression signatures that
distinguish between NF1-associated and sporadic
MPNSTs
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Survival lt12 mo. (n14) vs. gt24 mo. (n11) Survival lt12 mo. (n14) vs. gt24 mo. (n11) Survival lt12 mo. (n14) vs. gt24 mo. (n11)    
         
LocusLink ID Symbol Name FC P
5068 PAP Pancreatitis-associated protein -2.0 0.0005
4209 MEF2D MADS box transcription enhancer factor 2, polypeptide D -1.4 0.0002
8450 CUL4B Cullin 4B 1.7 0.0001
5532 PPP3CB Protein phosphatase 3, catalytic subunit, beta 2.0 0.0001
4664 NAB1 NGFI-A binding protein 1 2.2 0.0009
9122 SLC16A4 solute carrier family 16, member 4 3.9 0.0002
 
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EGFR(-)
EGFR()
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Group A NCAM, MBP, L1CAM, PLP1, BLBP, GAP43,
APO-D, RELN IGF2, FGFR1, MDK, CCNB1, CCNB2,
CCNF, Ki67 EGFR(-) more differentiated
phenotype
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• Conclusions
• NF1 loss is observed in both NF1-associated and
  sporadic MPNST
• CDKN2A inactivation is frequently observed in
  MPNST
• EGFR amplification is observed in one-third MPNST
• Expression profiling did not identify a molecular
  fingerprint that distinguishes NF1-associated
  from sporadic MPNST
• Expression profiling identified a molecular
  fingerprint for a subset of more aggressive
  MPNSTs
• Expression profiling identified a molecular
  fingerprint for a subset of MPNST with a more
  differentiated phenotype
• Future prospective studies will be required to
  determine whether these patterns of gene
  expression predict clinical behavior