Abstract
Nerve sheath tumors are the most common tumors of Neurofibromatosis type 1 (NF1) patients. Dermal neurofibromas develop in nearly all NF1‐patients, whereas plexiform neurofibromas are only observed in one‐third of the patients. NF1‐patients have about a 10% lifetime risk for developing malignant pheripheral nerve sheath tumors (MPNST). The origin of these tumors is thought to be the Schwann cell lacking functional neurofibromin. However, additional genetic alterations are likely to modulate tumor biology and to contribute to individual nerve sheath tumor entities. To gain insight into the molecular events and to determine whether these tumors can be classified according to gene expression profiles, we performed expression analysis applying cDNA array technology. Nine dermal neurofibromas, 7 plexiform neurofibromas, ten MPNST and two MPNST cell cultures were examined. All tumors but 6 sporadic MPNST were obtained from NF1‐patients. We detected significant differences in gene expression patterns between neurofibromas and MPNST and between dermal neurofibromas and plexiform neurofibromas. Tumor class prediction agreed in all but one case with histological and clinical classification. NF1‐associated and sporadic MPNST could not be distinguished by their gene expression patterns. We present a panel of discriminating genes that may assist subclassification of nerve sheath tumors.
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REFERENCES
- 1. Coindre JM, Trojani M, Contesso G, David M, Rouesse J, Bui NB, Bodaert A, De Mascarel I, De Mascarel A, Goussot JF (1986) Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer 58: 306–309. [DOI] [PubMed] [Google Scholar]
- 2. Crespi CL, Miller VP, Penman BW (1997) Microtiter plate assays for inhibition of human, drug‐metabolizing cytochromes P450. Anal Biochem 248: 188–190. [DOI] [PubMed] [Google Scholar]
- 3. DeClue JE, Heffelfinger S, Benvenuto G, Ling B, Li S, Rui W, Vass WC, Viskochil D, Ratner N (2000) Epidermal growth factor receptor expression in neurofibromatosis type 1‐related tumors and NF1 animal models. J Clin Invest 105: 1233–1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39: 311–314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Frahm S, Mautner V, Brems H, Legius E, Debiec‐Rychter M, Friedrich R, Knöfel W, Piper M, Kluwe L (2004) Genetic and phenotypic characterization of tumor cells derived from malignant peripheral nerve sheath tumors of neurofibromatosis 1 patients. Neurobiology of Disease (in press). [DOI] [PubMed] [Google Scholar]
- 6. Holtkamp N, Mautner V, Friedrich R, Harder A, Hartmann C, Theallier‐Janko A, Hoffmann K, von Deimling A (2004) Differentially expressed genes in neurofibromatosis 1‐associated neurofibromas and malignant peripheral nerve sheath tumors. Acta Neuropathol Berl 107: 159–168. [DOI] [PubMed] [Google Scholar]
- 7. Huson SM: (1994) Neurofibromatosis 1: a clinical and genetic overview. In: The Neurofibromatoses, Edited by Huson SM, Hughes RAC. pp 160–203, Chapman and Hall Medical, London . [Google Scholar]
- 8. Isaacs JS, Xu W, Neckers L (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3: 213–217. [DOI] [PubMed] [Google Scholar]
- 9. Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, Thomas M, Berdel WE, Serve H, Muller‐Tidow C (2003) MALAT‐1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early‐stage non‐small cell lung cancer. Oncogene 22: 8031–8041. [DOI] [PubMed] [Google Scholar]
- 10. Legius E, Dierick H, Wu R, Hall BK, Marynen P, Cassiman JJ, Glover TW (1994) TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer 10: 250–255. [DOI] [PubMed] [Google Scholar]
- 11. Kourea HP, Orlow I, Scheithauer BW, Cordon‐Cardo C, Woodruff JM (1999) Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. Am J Pathol 155: 1855–1860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. McFadyen MC, Cruickshank ME, Miller ID, McLeod HL, Melvin WT, Haites NE, Parkin D, Murray GI (2001) Cytochrome P450 CYP1B1 over‐expression in primary and metastatic ovarian cancer. Br J Cancer 85: 242–246. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP, Barker DF, Ledbetter DH, Kleider A, Martuza RL, Gusella JF, Seizinger BR (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in Recklinghausen neurofibromatosis. Proc Natl Acad Sci U S A 87: 5435–5439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Murray GI, Melvin WT, Greenlee WF, Burke MD (2001) Regulation, function, and tissue‐specific expression of cytochrome P450 CYP1B1. Annu Rev Pharmacol Toxicol 41:297–316. [DOI] [PubMed] [Google Scholar]
- 15. Murray GI, Taylor MC, McFadyen MC, McKay JA, Greenlee WF, Burke MD, Melvin WT (1997) Tumor‐specific expression of cytochrome P450 CYP1B1. Cancer Res 57: 3026–3031. [PubMed] [Google Scholar]
- 16. Neckers L (2002) Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8:S55–61. [DOI] [PubMed] [Google Scholar]
- 17. Perry A, Kunz SN, Fuller CE, Banerjee R, Marley EF, Liapis H, Watson MA, Gutmann DH (2002) Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms. J Neuropathol Exp Neurol 61: 702–709. [DOI] [PubMed] [Google Scholar]
- 18. Perry A, Roth KA, Banerjee R, Fuller CE, Gutmann DH (2001) NF1 deletions in S‐100 protein‐positive and negative cells of sporadic and neurofibromatosis 1 (NF1)‐associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. Am J Pathol 159: 57–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Rochat B, Morsman JM, Murray GI, Figg WD, McLeod HL (2001) Human CYP1B1 and anticancer agent metabolism: mechanism for tumor‐specific drug inactivation J Pharmacol Exp Ther 296: 537–541. [PubMed] [Google Scholar]
- 20. Serra E, Rosenbaum T, Winner U, Aledo R, Ars E, Estivill X, Lenard HG, Lazaro C (2000) Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum Mol Genet 9: 3055–3064. [DOI] [PubMed] [Google Scholar]
- 21. Shimada T, Hayes CL, Yamazaki H, Amin S, Hecht SS, Guengerich FP, Sutter TR (1996) Activation of chemically diverse procarcinogens by human cytochrome P‐450 1B1. Cancer Res 56: 2979–2984. [PubMed] [Google Scholar]
- 22. Tibshirani R, Hastie T, Narasimhan B, Chu G (2002) Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci U S A 99: 6567–6572. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Upadhyaya M, Han S, Consoli C, Majounie E, Horan MP, Thomas N, Potts C, Griffiths S, Ruggiere M, von Deimling A, Cooper D (2004) Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors. Hum Mutat 23: 134–146. [DOI] [PubMed] [Google Scholar]