WJNS  Vol.5 No.2 , May 2015
Correlation of Unilateral Sporadic Vestibular Schwannoma Growth Rates with Genetic and Immunohistochemical Abnormalities
ABSTRACT
Background: Unilateral sporadic vestibular schwannomas (USVS) are caused by inactivating somatic mutations of both alleles of the neurofibromatosis 2 (NF2) tumor suppressor gene. Unilateral sporadic vestibular schwannomas have a widely-varying growth patterns whose causes are poorly understood. Objective: We examined the relationships between an index of USVS growth, and genetic abnormalities and pathological growth indices. Subjects and Methods: Single-strand conformational polymorphism analysis and heteroduplex methods were used to screen for mutations in all 17 exons of the NF2 gene in USVS from 63 patients. Loss of heterozygosity (LOH) analyses were also carried out. An index of USVS growth (clinical growth index, CGI) was calculated as maximum tumor diameter divided by duration of symptoms. The immunohistochemical growthindices were based on monoclonal antibodies to Ki-67 and another tumor cell proliferation marker (platelet-derived growth factor (PDGF)). Results: CGI was highly variable and did not significantly decrease with increasing age at diagnosis. Either somatic NF2 mutations or LOH was found in 88% of tumors. PDGF and Ki-67 increased significantly with increasing age at diagnosis, and PDGF was lower in tumors with LOH than in those without LOH. In multiple linear regression analysis, CGI was significantly higher in people with higher PDGF, after accounting for age at diagnosis and LOH. Conclusion: An index of USVS growth increases with increasing PDGF, after accounting for age and LOH.

Cite this paper
Mohyuddin, A. , Baser, M. , Ramsden, R. and Evans, D. (2015) Correlation of Unilateral Sporadic Vestibular Schwannoma Growth Rates with Genetic and Immunohistochemical Abnormalities. World Journal of Neuroscience, 5, 155-161. doi: 10.4236/wjns.2015.52017.
References
[1]   Moffat, D.A., Hardy, D.G. and Bagueley, D.M. (1989) Strategy and Benefits of Acoustic Neuroma Searching. The Journal of Laryngology & Otology, 103, 51-59.
http://dx.doi.org/10.1017/S0022215100108023

[2]   Tos, M., Charabi, S. and Thomsen, J. (1999) Incidence of Vestibular Schwannomas. Laryngoscope, 109, 736-740. http://dx.doi.org/10.1097/00005537-199905000-00011

[3]   Rouleau, G.A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., et al. (1993) Alteration in a New Gene Encoding a Putative Membrane-Organizing Protein Causes Neurofibromatois Type 2. Nature, 363, 515-521.
http://dx.doi.org/10.1038/363515a0

[4]   Trofatter, J.A., MacCollin, M.M., Rutter, J.L., Murrell, J.R., Duyao, M.P., Parry, D.M., Eldridge, R., Kley, N., Menon, A.G., Pulaski, K., et al. (1993) A Novel Moesin-, Ezrin-, Radixin-Like Gene Is a Candidate for the Neurofibromatosis 2 Tumor Suppressor. Cell, 72, 791-800.
http://dx.doi.org/10.1016/0092-8674(93)90406-G

[5]   Irving, R.M., Moffat, D., Hardy, D.G., Barton, D.E., Xuereb, J.H. and Maher, E.R. (1994) Somatic NF2 Gene Mutations in Familial and Non-Familial Vestibular Schwannoma. Human Molecular Genetics, 3, 347-350. http://dx.doi.org/10.1093/hmg/3.2.347

[6]   Lanser, M.J., Sussman, S.A. and Frazer, K. (1992) Epidemiology, Pathogenesis and Genetics of Acoustic Tumors. Otolaryngol Clin North Am, 25, 499-520.

[7]   Bederson, J.B., von Ammon, K., Wichmann, W.W. and Yasargil, M.G. (1991) Conservative Treatment of Patients with Acoustic Tumors. Neurosurgery, 28, 646-651. http://dx.doi.org/10.1227/00006123-199105000-00002

[8]   Sterkers, O., El Dine, M.B., Martin, N., Viala, P. and Sterkers, J.M. (1991) Slow versus Rapid Growth in Acoustic Neuromas. In: Tos, M. and Thomsen, J., Eds., Proceedings of the First International Conference on Acoustic Neuroma, Kugler Publications, Amsterdam, 3-6.

[9]   Nedzelski, J.M., Schessel, D.A., Pfleiderer, A., Kassel, E.E. and Rowed, D.W. (1992) Conservative Management of Acoustic Neuromas. Otolaryngol Clin North Amer, 25, 691-705.

[10]   Wazen, J., Silverstein, H., Norrell, H. and Besse, B. (1985) Preoperative and Postoperative Growth Rates in Acoustic Neuromas Documented with CT Scanning. Otolaryngology—Head and Neck Surgery, 93, 151-155.

[11]   Silverstein, H., McDaniel, A., Norrell, H. and Wazen, J. (1985) Conservative Management of Acoustic Neuroma in the Elderly Patient. Laryngoscope, 95, 766-770. http://dx.doi.org/10.1288/00005537-198507000-00002

[12]   Clark, W.C., Moretz, W.H., Acker, J.D., Gardner, L.G., Eggers, F. and Robertson, J.H. (1985) Nonsurgical Management of Small and Intracanalicular Acoustic Tumors. Neurosurgery, 16, 801-803. http://dx.doi.org/10.1227/00006123-198506000-00011

[13]   Mautner, V.F., Baser, M.E., Thakker, S.D., Feiger, U.M., Freidman, J.M. and Kluwe, L. (2002) Vestibular Schwannoma Growth in Patients with Neurofibromatosis Type 2: A Longitudinal Study. Journal of Neurosurgery, 96, 223-228. http://dx.doi.org/10.3171/jns.2002.96.2.0223

[14]   Baser, M.E., Makariou, E.V. and Parry, D.M. (2002) Predictors of Vestibular Schwannoma Growth in Patients with Neurofibromatosis Type 2. Journal of Neurosurgery, 96, 217-222.
http://dx.doi.org/10.3171/jns.2002.96.2.0217

[15]   Antinheimo, J., Haapasalo, H., Sepp?la, M., Sainio, M., Carpen, O. and J??skenl?inen, J. (1995) Proliferative Potential of Sporadic and Neurofibromatosis 2-Associated Schwannomas as Studied by MIB-1 (Ki-67) and PCNA Labeling. Journal of Neuropathology and Experimental Neurology, 54, 776-782. http://dx.doi.org/10.1097/00005072-199511000-00004

[16]   Sobel, R.A. (1993) Vestibular (Acoustic) Schwannomas: Histologic Features in Neurofibromatosis 2 and in Unilateral Cases. Journal of Neuropathology and Experimental Neurology, 52, 106-113. http://dx.doi.org/10.1097/00005072-199303000-00002

[17]   Wu, C.L., Tahkker, N., Neary, W., Black, G., Lye, R., Ramsden, R.T., Read, A.P. and Evans, D.G. (1998) Differential Diagnosis of Type 2 Neurofibromatosis: Molecular Discrimination of NF2 and Sporadic Vestibular Schwannomas. Journal of Medical Genetics, 35, 973-977.
http://dx.doi.org/10.1136/jmg.35.12.973

[18]   Hsu, S.M., Raine, L. and Fanger, H. (1981) The Use of Antiavidin Antibody and Avidin-Biotin-Peroxidase Complex in Immunoperoxidase Technics. American Journal of Clinical Pathology, 75, 816-821.

[19]   Jacoby, L.B., MacCollin, M.M., Louis, D.N., Mohney, T., Rubio, M.P., Pulaski, K., Trofatter, J.A., Kley, N., Seizinger, B. and Ramesh, V. (1994) Exon Scanning for Mutation of the NF2 Gene in Schwannomas. Human Molecular Genetics, 3, 413-419. http://dx.doi.org/10.1093/hmg/3.3.413

[20]   Mohyuddin, A., Neary, W.J., Wallace, A., Wu, C.L., Read, A., Ramsden, R.T. and Evans, D.G.R. (2002) Molecular Genetic Analysis of the NF2 Gene in Young Patients with Unilateral Vestibular Schwannomas. Journal of Medical Genetics, 39, 315-322. http://dx.doi.org/10.1136/jmg.39.5.315

[21]   Wallace, A.J. (1997) Combined Single Strand Conformation Polymorphism and Heteroduplex Analysis. In: Taylor, G.R., Ed., Laboratory Methods for the Detection of Mutations and Polymorphism in DNA, CRC Press, Boca Raton, 79-94.

[22]   Weissenbach, J. (1993) A Second Generation Linkage Map of the Human Genome Based on Highly Informative Microsatellite Loci. Gene, 135, 275-278. http://dx.doi.org/10.1016/0378-1119(93)90077-G

[23]   Bourn, D. and Strachan, T. (1995) Highly Polymorphic Dinucleotide Repeat at the NF2 Gene. Human Genetics, 95, 712. http://dx.doi.org/10.1007/BF00209494

[24]   Marineau, C., Baron, C., Delattre, O., Zucman, J., Thomas, G. and Rouleau, G.A. (1993) Dinucleotide Repeat Polymorphism at the D22S268 Locus. Human Molecular Genetics, 2, 336.
http://dx.doi.org/10.1093/hmg/2.3.336-a

[25]   Gyapay, G., Morissette, J., Vignal, A., Dib, C., Fizames, C., Millasseau, P., Marc, S., Bernardi, G., Lathrop, M. and Weissenbach, J. (1994) The 1993-94 Genethon Human Genetic Linkage Map. Nature Genetics, 7, 246-339. http://dx.doi.org/10.1038/ng0694supp-246

[26]   Schuler, G.D., Boguski, M.S., Stewart, E.A., Stein, L.D., Gyapay, G., Rice, K., White, R.E., Rodriguez-Tome, P., Aggarwal, A., Bajorek, E., Bentolila, S., Birren, B.B., Butler, A., Castle, A.B., Chiannikulchai, N., Chu, A., Clee, C., Cowles, S., Day, P.J., Dibling, T., Drouot, N., Dunham, I., Duprat, S., East, C. and Hudson, T.J. (1996) A Gene Map of the Human Genome. Science, 274, 540-546.
http://dx.doi.org/10.1126/science.274.5287.540

[27]   Rubin, K., Tingstrom, A., Hansson, G.K., Larsson, E., Ronnstrand, L., Klareskog, L., Claesson-Welsh, L., Heldin, C.H., Fellstrom, B. and Terracio, L. (1988) Induction of B-Type Receptors for Platelet-Derived Growth Factor in Vascular Inflammation: Possible Implications for Development of Vascular Proliferative Lesions. The Lancet, 1, 1353-1356. http://dx.doi.org/10.1016/S0140-6736(88)92177-0

[28]   Fajardo, L.F., Kwan, H.H., Kowalski, J., Prionas, S.D. and Allison, A.C. (1992) Dual Role of Tumor Necrosis Factor-Alpha in Angiogenesis. The American Journal of Pathology, 140, 539-544.

[29]   Weerda, H.G., Gamberger, T.I., Siegner, A., Gjuric, M. and Tamm, E.R. (1998) Effects of Transforming Growth Factor-Beta1 and Basic Fibroblast Growth Factor on Proliferation of Cell Cultures Derived from Human Vestibular Nerve Schwannoma. Acta Oto-Laryngologica, 118, 337-343.
http://dx.doi.org/10.1080/00016489850183412

[30]   Gerdes, J., Lemke, H., Baisch, H., Wacker, H.H., Schwab, U. and Stein, H. (1984) Cell Cycle Analysis of a Cell Proliferation-Associated Human Nuclear Antigen Defined by the Monoclonal Antibody Ki-67. The Journal of Immunology, 133, 1710-1715.

[31]   Charabi, S., Engel, P., Jacobson, G.K., Tos, M. and Thomsen, J. (1993) Growth Rate of Acoustic Neuroma Expressed by Ki-67 Nuclear Antigen versus Symptom Duration. Annals of Otology, Rhinology & Laryngology, 102, 805-809. http://dx.doi.org/10.1177/000348949310201013

[32]   Charabi, S., Engel, P., Charabi, B., Jacobsen, G.K., Overgaard, J., Thomsen, J. and Tos, M. (1996) Growth of Vestibular Schwannomas: In Situ Model Employing the Monoclonal Antibody Ki-67 and DNA Flow Cytometry. American Journal of Otolaryngology, 17, 301-306.

[33]   Lottrich, M., Mawrin, C., Chamaon, K., Kirches, E., Dietzmann, K. and Freigang, B. (2007) Expression of Transforming Growth Factor-β Receptor Type 1 and 2 in Human Sporadic Vestibular Schwannoma. Pathology—Research and Practice, 203, 245-249. http://dx.doi.org/10.1016/j.prp.2006.12.007

[34]   Irving, R.M., Harada, T., Moffat, D.A., Hardy, D.G., Whittaker, J.L., Xuereb, J.H. and Maher, E.R. (1997) Somatic Neurofibromatosis Type 2 Gene Mutations and Growth Characteristics in Vestibular Schwannoma. American Journal of Otolaryngology, 18, 754-760.

[35]   MacCollin, M.M., Ramesh, V., Jacoby, L.B., Louis, D.N., Rubio, M.P., Pulaski, K., Trofatter, J.A., Short, M.P., Bove, C. and Eldridge, R. (1994) Mutational Analysis of Patients with Neurofibromatosis 2. The American Journal of Human Genetics, 55, 314-320.

[36]   Gutmann, D.H., Hirbe, A.C. and Haipek, C.A. (2001) Functional Analysis of Neurofibromatosis 2 (NF2) Missense Mutations. Human Molecular Genetics, 10, 1519-1529.
http://dx.doi.org/10.1093/hmg/10.14.1519

[37]   Kino, T., Takeshima, H., Nakao, M., Nishi, T., Yamamoto, K., Kimura, T., Saito, Y., Kochi, M., Kuratsu, J., Saya, H. and Ushio, Y. (2001) Identification of the Cis-Acting Region in the NF2 Gene Promoter as a Potential Target for Mutation and Methylation-Dependent Silencing in Schwannoma. Gene Cells, 6, 441-454. http://dx.doi.org/10.1046/j.1365-2443.2001.00432.x

 
 
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