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Mark A. Watson, Arie Perry, and David H. Gutmann Washington University School of Medicine

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

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Mark A. Watson, Arie Perry, and David H. Gutmann Washington University School of Medicine

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  1. 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

  2. MPNST • Devastating tumor • Poor response to therapy • Poor patient survival • Patients with neurofibromatosis 1 (NF1) harbor 10% lifetime risk of developing MPNST

  3. NF1 loss seen in 76% MPNST by FISH • Neurofibromin loss seen in 9/9 MPNST NF1 inactivation is critical event in MPNST pathogenesis

  4. p16 deletion in MPNSTs Tumorp16 deletionp16 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

  5. Benign Neurofibromas Malignant Peripheral Nerve Sheath Tumors DG102 DG206 WU33 1570 2157 5628 6218 6696 8235 MB 511 KL DP 19 EGF-R EGFR amplification in MPNSTs CEP7 EGFR TumorEGF-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

  6. Gene expression profiling 25 NF1-associated 17 sporadic tumors Genetic signature to distinguish NF1-associated from sporadic? Genetic signature to predict clinical behavior?

  7. 4247 4263 4260 4236 4252 4261424042744262425742414258 4238 4239 4276 42704235 4244 4266 42694251423042644271 4232 4242 4245 423142554234425342334254423742564265424342594246425042484275424942684267 SIAT9 MGLL GCM1 SGCE SEC14L1 DDX21 SSSSSSSSSsnssSsnsnNnnnNnnnsNNnsNsnnNNnnnNNnNn Few, if any, gene expression signatures that distinguish between NF1-associated and sporadic MPNSTs

  8. EGFR Expression Sporadic (n=17) NF1 (n=25) EGFR(-) EGFR(+)

  9. Group A NCAM, MBP, L1CAM, PLP1, BLBP, GAP43, APO-D, RELN IGF2, FGFR1, MDK, CCNB1, CCNB2, CCNF, Ki67 EGFR(-) “more differentiated phenotype”

  10. 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

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