Author(s) Asad Aslam Khan, Riffat Mehboob, Mulazim Hussain Bukhari

Affiliation(s)
Department of Ophthalmology, King Edward Medical University, Lahore, Pakistan.
Department of Pathology, King Edward Medical University, Lahore, Pakistan.

ABSTRACT

Retinoblastoma (Rb) was reported firstly by Benedict is the commonest pediatric intraocular malignant tumor in children younger than 5 years of age. The study was conducted to detect the RB-1 gene for prognostic evaluation in retinoblastoma and to see the frequency of RB-1 gene in our population. This was a retrospective descriptive analytical study. Five years biopsies (January, 2006 to December 2011) of the retinoblastoma, from the Pathology department, was retrieved to see optic nerve involvement in all the retrieved specimens. The study was taken to see the mutation of RB1 gene by immunohistochemistry and PCR. The study plan was approved from Institutional Review Board (IRB) of the University. All the cases showed positivity of abnormal Rb-1 gene proteins expression by Immunohistochemistry staining. On PCR, 51/52 (98%) tumors expressed gene mutation as compared to 100% expression shown by IHC. Out of these, 28/51 (55%) cases showed ONI and ODI with positivity for mutated RB gene. A positive association was seen among RB gene mutation with ONI and ODI (p = 0.05). There were 33/51 (65%) cases who did not show any EOE but showed PCR positivity for RB gene mutation. While there were 18/51 (35%) cases who showed EOE and positivity of PCR for Rb-1 gene mutation and a positive association was seen with EOE and gene mutation (p = 0.005). The most common sequence of mutation was on 13 with 33 cases for double mutation, 12 cases for single and 6 patients for triple pattern of mutation. Most of the double and triple sequences of mutations were associated with ONI, ODI and EOE. We concluded that mutation of RB-1 gene is responsible in causation of the tumors with a positive association with tumor size and tumor extension (optic nerve, and extraocular extension), and mutation affects patients with all ages, both gender and unilateral and bilateral tumors.

KEYWORDS
Retinoblastoma; RB-1 Gene; Optic Nerve; Optic Disc; Extra-Occular Extention; PCR; Immunohistochemistry; Sequencing

Cite this paper
Khan, A. , Mehboob, R. and Bukhari, M. (2013) Prognostic significance of retinoblastoma gene mutation in retinoblastoma eye with respect to pathological risk factors. Natural Science, 5, 411-418. doi: 10.4236/ns.2013.53054.

References
[1]   Abidi, O., Knari, S., Sefri, H., Charif, M., Senechal, A., Hamel, C., et al. (2011) Mutational analysis of the RB1 gene in Moroccan patients with retinoblastoma. Molecular Vision, 17, 3541-3547.

[2]   Yun, J., Li, Y., Xu, C.T. and Pan, B.R. (2011) Epidemiology and Rb1 gene of retinoblastoma. International Journal of Ophthalmology, 4, 103-109.

[3]   Knudson Jr., A.G. (1971) Mutation and cancer: Statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America, 68, 820-823. doi:10.1073/pnas.68.4.820

[4]   Broaddus, E., Topham, A. and Singh, A.D. (2009) Incidence of retinoblastoma in the USA: 1975-2004. The British journal of Ophthalmology, 93, 21-23. doi:10.1136/bjo.2008.138750

[5]   Rushlow, D., Piovesan, B., Zhang, K., Prigoda-Lee, N.L., Marchong, M.N., Clark, R.D., et al. (2009) Detection of mosaic RB1 mutations in families with retinoblastoma. Human Mutation, 30, 842-851. doi:10.1002/humu.20940

[6]   Abouzeid, H., Munier, F.L,, Thonney, F. and Schorderet, D.F. (2007) Ten novel RB1 gene mutations in patients with retinoblastoma. Molecular Vision, 13, 1740-1745.

[7]   Moll, A.C., Imhof, S.M., Meeteren A.Y.S.-V., Kuik, D.J., Hofman, P. and Boers, M. (2001) Second primary tumors in hereditary retinoblastoma: A register-based study, 1945- 1997: Is there an age effect on radiation-related risk? Ophthalmology, 108, 1109-1114. doi:10.1016/S0161-6420(01)00562-0

[8]   Sovinz, P., Urban, C., Lackner, H., Benesch, M. and Langmann, G. (2006) Retinoblastoma: A proposal for a multimodal treatment concept for intraocular retinoblastoma in Austria. Wiener Klinische Wochenschrift, 118, 22- 30. doi:10.1007/s00508-005-0503-z

[9]   Kumamoto, H. and Ooya, K. (2006) Immunohistochemical detection of retinoblastoma protein and E2 promoter- binding factor-1 in ameloblastomas. Journal of Oral Pathology & Medicine, 35, 183-189. doi:10.1111/j.1600-0714.2006.00381.x

[10]   Massaro-Giordano, M., Baldi, G., De Luca, A., Baldi, A. and Giordano, A. (1999) Differential expression of the retinoblastoma gene family members in choroidal melanoma: Prognostic significance. Clinical Cancer Research, 5, 1455-1458.

[11]   Bignon, Y.J., Chen, Y., Chang, C.Y., Riley, D.J., Windle, J.J., Mellon, P.L., et al. (1993) Expression of a retinoblastoma transgene results in dwarf mice. Genes & Development, 7, 1654-1662. doi:10.1101/gad.7.9.1654

[12]   Cance, W.G., Brennan, M.F., Dudas, M.E., Huang, C.M. and Cordon-Cardo, C. (1990) Altered expression of the retinoblastoma gene product in human sarcomas. New England Journal of Medicine, 323, 1457-1462. doi:10.1056/NEJM199011223232105

[13]   Lohmann, D. (2010) Retinoblastoma. Advances in Experimental Medicine and Biology, 685, 220-227. doi:10.1007/978-1-4419-6448-9_21

[14]   Lohmann, D.R., Brandt, B., Hopping, W., Passarge, E. and Horsthemke, B. (1996) The spectrum of RB1 germline mutations in hereditary retinoblastoma. American Journal of Human Genetics, 58, 940-949.

[15]   Chintagumpala, M., Chevez-Barrios, P., Paysse, E.A., Plon, S.E. and Hurwitz, R. (2007) Retinoblastoma: Review of current management. The Oncologist, 12, 1237- 1246. doi:10.1634/theoncologist.12-10-1237

[16]   Eagle Jr., R.C. (2013) The pathology of ocular cancer. Eye (London, England), 27, 128-136.

[17]   Nichols, K.E., Walther, S., Chao, E., Shields, C. and Ganguly, A. (2009) Recent advances in retinoblastoma genetic research. Current Opinion in Ophthalmology, 20, 351- 355. doi:10.1097/ICU.0b013e32832f7f25

[18]   Laurie, N., Mohan, A., McEvoy, J., Reed, D., Zhang, J., Schweers, B., et al. (2009) Changes in retinoblastoma cell adhesion associated with optic nerve invasion. Molecular and Cellular Biology, 29, 6268-6282. doi:10.1128/MCB.00374-09

[19]   Vandhana, S., Lakshmi, T.S., Indra, D., Deepa, P.R. and Krishnakumar, S. (2012) Microarray analysis and biochemical correlations of oxidative stress responsive genes in retinoblastoma. Current Eye Research, 37, 830-841. doi:10.3109/02713683.2012.678544

[20]   Chevez-Barrios, P., Hurwitz, M.Y., Louie, K., Marcus, K.T., Holcombe, V.N., Schafer, P., et al. (2000) Metastatic and nonmetastatic models of retinoblastoma. The American Journal of Pathology, 157, 1405-1412. doi:10.1016/S0002-9440(10)64653-6

[21]   Houdayer, C., Gauthier-Villars, M., Lauge, A., PagesBerhouet, S., Dehainault, C., Caux-Moncoutier, V., et al. (2004) Comprehensive screening for constitutional RB1 mutations by DHPLC and QMPSF. Human Mutation, 23, 193-202. doi:10.1002/humu.10303

[22]   Richter, S., Vandezande, K., Chen, N., Zhang, K., Sutherland, J., Anderson, J., et al. (2003) Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. American Journal of Human Genetics, 72, 253-269. doi:10.1086/345651

[23]   Hogg, A., Onadim, Z., Baird, P.N. and Cowell, J.K. (1992) Detection of heterozygous mutations in the RB1 gene in retinoblastoma patients using single-strand conformation polymorphism analysis and polymerase chain reaction sequencing. Oncogene, 7, 1445-1451.

[24]   Shimizu, T., Toguchida, J., Kato, M.V., Kaneko, A., Ishizaki, K. and Sasaki, M.S. (1994) Detection of mutations of the RB1 gene in retinoblastoma patients by using exon-by-exon PCR-SSCP analysis. American Journal of Human Genetics, 54, 793-800.