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

33KL D

P19 15

7021

5756

2862

1866

9682

35

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)

EGFR

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