mark a. watson, arie perry, and david h. gutmann washington university school of medicine
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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 - PowerPoint PPT PresentationTRANSCRIPT
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
MPNST
•Devastating tumor•Poor response to therapy•Poor patient survival•Patients with neurofibromatosis 1 (NF1) harbor 10% lifetime risk of developing MPNST
•NF1 loss seen in 76% MPNST by FISH
•Neurofibromin loss seen in 9/9 MPNST
NF1 inactivation is critical event in MPNST pathogenesis
p16 deletion in MPNSTs
J. Neuropath Exp. Neurol., 2002
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%)
CEP9p16
EGFR amplification in MPNSTs
J. Neuropath Exp. Neurol., 2002
Tumor EGF-R amplification
Schwannoma 0/5Plexiform neurofibroma 0/13
MPNST 5/19
(26%)
Synovial sarcoma 0/7 Fibrosarcoma 0/6 Hemangiopericytoma 0/13
MB
DG
206
WU
33
KL
DP
19
1570
2157
5628
6218
6696
8235
511
BenignNeurofibromas
Malignant PeripheralNerve Sheath Tumors
EGF-R
DG
102
CEP7EGFR
Gene expression profiling25 NF1-associated17 sporadic tumors
Genetic signature to distinguish NF1-associated from sporadic?
Genetic signature to predict clinical behavior?
SSSSSSSSSsnssSsnsnNnnnNnnnsNNnsNsnnNNnnnNNnNn
4247
4263
4260
4236
4252
4261
4240
4274
4262
4257
4241
4258
4238
4239
4276
4270
4235
4244
4266
4269
4251
4230
4264
4271
4232
4242
4245
4231
4255
4234
4253
4233
4254
4237
4256
4265
4243
4259
4246
4250
4248
4275
4249
4268
4267
SIAT9MGLLGCM1SGCESEC14L1DDX21
Few, if any, gene expression signatures that distinguish between NF1-associated and sporadic
MPNSTs
Survival <12 mo. (n=14) vs. >24 mo. (n=11)
LocusLink ID Symbol Name FC P
5068 PAP Pancreatitis-associated protein -2.00.000
5
4209 MEF2DMADS box transcription enhancer factor 2, polypeptide D -1.4
0.0002
8450 CUL4B Cullin 4B 1.70.000
1
5532 PPP3CB Protein phosphatase 3, catalytic subunit, beta 2.00.000
1
4664 NAB1 NGFI-A binding protein 1 2.20.000
9
9122 SLC16A4 solute carrier family 16, member 4 3.90.000
2
Sporadic
(n=17)
NF1
(n=25)
EG
FR
Exp
ress
ion
EGFR(-)
EGFR(+)
Group A
NCAM, MBP, L1CAM, PLP1, BLBP, GAP43, APO-D, RELN
IGF2, FGFR1, MDK, CCNB1, CCNB2, CCNF, Ki67
EGFR(-)
“more differentiated phenotype”
Conclusions
1. NF1 loss is observed in both NF1-associated and sporadic MPNST
2. CDKN2A inactivation is frequently observed in MPNST3. EGFR amplification is observed in one-third MPNST4. Expression profiling did not identify a molecular
fingerprint that distinguishes NF1-associated from sporadic MPNST
5. Expression profiling identified a molecular fingerprint for a subset of more aggressive MPNSTs
6. Expression profiling identified a molecular fingerprint for a subset of MPNST with a more differentiated phenotype
7. Future prospective studies will be required to determine whether these patterns of gene expression predict clinical behavior