Retinoblastoma pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Retinoblastoma is a cancer of the retina. Development of this tumor is initiated by mutations[1] that inactivate both copies of the RB1 gene, which codes for the retinoblastoma protein.[2]. The Retinoblastoma gene acts as a tumor suppressor gene. The RB1 gene is composed of 27 exons which encodes for a 110kd nuclear phosphoprotein.[3] The cDNA fragment detects atleast 70 kilobases(kb) in human chromosome band 13q14 of which a part of it or complete 70 kilobases in that band are frequently deleted in retinoblastomas and osteosarcomas.[4]
In addition to the RB1 gene deletion, a number of studies also indicated other molecular events are necessary for genesis of tumor.[5][6]
Function of retinoblastoma proteins
The proteins derived from RB gene play a key role in regulating advancement of cell cycle from G1 to S phases. These proteins negatively regulate two important positive regulators of cell cycle entry, E2F transcription factors and Cyclin dependent kinases. RB proteins repress the transcriptional activity of E2Fs in growth arrested cells. Positive growth factor signaling leads to activation of cyclin dependent kinases which inturn phosporylte the RB proteins inactivating them which will lead to E2F activation and additional cyclin dependent activity. The end result is the cell cycle is propelled forward irreversibly leading to DNA synthesis.[7].
So, when there is a deletion of RB gene, the RB proteins no more present which leads to unhindered cell proliferation leading to tumors.
Genetics
Retinoblastoma is inherited in autosomal dominant fashion. Each child of a parent with familial bilateral retinoblastoma has a 50% risk of inheriting the retinoblastoma gene. The penetrance of retinoblastoma is usually 90%. Genetic modifiers and partial inactivation of RB gene may sometimes lead to lower penetrance.
Knudson's two hit hypothesis and retinoblastoma:
In 1971, Alfred Knudson proposed his "two-hit" theory based upon empiric observations of the clinical genetics of Rb, revealing the role of tumor-suppressor genes in human cancer. Knudson proposed that
In the dominant inherited form of Rb, one mutation is inherited via germ line and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells.[8]
The Knudson hypothesis was validated later with the cloning of RB1, the first tumor-suppressor gene to be identified.
Pathology
References
- ↑ Knudson A (1971). "Mutation and cancer: statistical study of retinoblastoma". Proc Natl Acad Sci U S A. 68 (4): 820–3. PMID 5279gadgqetqer523 Check
|pmid=value (help). - ↑ Friend S, Bernards R, Rogelj S, Weinberg R, Rapaport J, Albert D, Dryja T. "A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma". Nature. 323 (6089): 643–6. PMID 2877398.
- ↑ Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, Brisse H, Doz F, Desjardins L (2006). "Retinoblastoma". Orphanet Journal of Rare Diseases. 1: 31. doi:10.1186/1750-1172-1-31. PMC 1586012. PMID 16934146. Retrieved 2012-05-03.
- ↑ Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP (1986). "A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma". Nature. 323 (6089): 643–6. doi:10.1038/323643a0. PMID 2877398. Retrieved 2012-05-03.
- ↑ Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange DE, Radlwimmer B, Lohmann DR, Lichter P (2005). "Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization". Genes, Chromosomes & Cancer. 43 (3): 294–301. doi:10.1002/gcc.20186. PMID 15834944. Retrieved 2012-05-03. Unknown parameter
|month=ignored (help) - ↑ Mairal A, Pinglier E, Gilbert E, Peter M, Validire P, Desjardins L, Doz F, Aurias A, Couturier J (2000). <370::AID-GCC2>3.0.CO;2-8 "Detection of chromosome imbalances in retinoblastoma by parallel karyotype and CGH analyses". Genes, Chromosomes & Cancer. 28 (4): 370–9. PMID 10862045. Retrieved 2012-05-03. Unknown parameter
|month=ignored (help) - ↑ Henley SA, Dick FA (2012). "The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle". Cell Division. 7 (1): 10. doi:10.1186/1747-1028-7-10. PMC 3325851. PMID 22417103. Retrieved 2012-05-03.
- ↑ Sábado Alvarez C (2008). "Molecular biology of retinoblastoma". Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 10 (7): 389–94. PMID 18628066. Unknown parameter
|month=ignored (help);|access-date=requires|url=(help)