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The Biology of Retinoblastoma

Paper Type: Free Essay Subject: Biology
Wordcount: 2290 words Published: 23rd Sep 2019

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The Biology of Retinoblastoma


Abstract :

Retinoblastoma (RB) is one of the most common intraocular malignancy tumors that occur during childhood and infancy. There are two forms: heritable and non-heritable. The RB gene is located on chromosome 13 and it produces a protein (pRb) responsible for the regulation of the cell cycle. The theory of “the two hits” explains the occurrence of this disease. Several types of mutation can inactivate both alleles of the retinoblastoma gene and therefore cause a tumor. Point mutations are the most commons type of mutations associated with retinoblastoma. According to its size and localization, tumors are classified by groups. The diagnosis of the disease is essentially clinical. Multiple treatments exist such as chemotherapy, laser, radiotherapy, external beam and as a last resource enucleation. Nowadays, clinicians are trying to optimize its treatment by reinforcing the efficiency of directed chemotherapy with minimal side effects. In the future, a better understanding of the molecular biology of retinoblastoma will allow us to improved therapeutic treatments.


Introduction :

Retinoblastoma (RB) is a disease of early childhood, most of the cases are discovered by the age of 5.

It affects the retina of the child in one eye (unilateral) or in both eyes (multilateral). Studies have shown that disease incidence is around 1 in 20000 live births.

Overall, 40% of the retinoblastoma patients have hereditary retinoblastoma, the other 60% have non-hereditary retinoblastoma. (In the hereditary form, the two eyes are usually affected whereas in the non-hereditary form only one eye is touched.)

In both cases, the most commons symptoms are leukocoria (a white reflex of the pupil) and strabismus (squint eyes). Leukocoria is only visible under certain light conditions. In some cases, parents find out their child have leukocoria by taking pictures of them. Indeed, in case of leukocoria the fight of the flash colours the eye in white instead of red. As for strabismus, it is easy to diagnose and it reflects the weakness of the vision.

The people affected by retinoblastoma have an abnormal karyotype, with a mutation of the Rb1 gene in the locus 14.2 of chromosome 13. The earlier the diagnostic of the disease, the more the patient maintains his vision and lives a safe life.

The RB1 gene and its protein action on the cell cycle:

As previously mentioned, the Rb1 gene is located at the locus 14.2 of the chromosome 13. It is a tumor suppressor gene composed of 27 exons. Tumor suppressor genes encode molecules involved in the regulation of the cell cycle. There are two tumor suppressor genes that regulate directly the cell cycle: the retinoblastoma gene and the p53 gene.

The Rb gene produces the Rb protein (pRb) responsible of the regulation of the cell cycle. The cell cycle consists of 4 phases: G1, S, G2, and the mitosis. At the end of a cell cycle the DNA of the cell will be replicated. This process is true for each of nucleated cells of the body. When the cells are not cycling they are at phase G0 so to re-enter the cycle the cells need to received intra and extracellular signals. When the cell reaches the checkpoint G1 to enter the S phase it needs to build the proteins or enzymes necessary for the DNA replication. To do so, the protein E2F, binds to the DNA sequence to allow its transcription. This protein E2F, also called a transcription factor, binds itself to the pRB protein to form a complex (1) The function of the pRB protein is to inactivate the E2F protein in order to stop the replication of the cell DNA, as a consequence, the cell cycle doesn’t reach the G1 checking point. For the cells to divide further, the pRB protein needs to be inactivated. This is achieved through a process called phosphorylation, during which a phosphate group is added to the protein. The transcription factor E2F can then allow the cells to go to the phase S, and controls the rest of the cell division.

However, if the gene Rb is mutated, then the pRB protein formed might not be recognized. Therefore, it won’t combined with the E2F protein, and this transcription factor will be allowed to move the cells directly to phase S with an uncontrolled cell division.


In the 70’s Alfred Knudson made a theory called « the two hit » where he proposed that in the inherited form of Rb, one mutation is inherited via one of the parents: this is called the « first hit », and the second occurs in somatic cells. In the non-hereditary form, both mutations occur in somatic cells randomly. The « two hits » means that the tumor formation occurs after two mutations. They are two alleles in the Rb gene in every nucleated cell of the body (2).

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In the hereditary form, one of the parents carries a mutated non-functioning Rb gene that is transmitted to the child. Every cell of the child’s body will therefore be carrying one faulty copy of the Rb gene. The cells of the child will only develop the tumor after the remaining other normal copy is mutated, which corresponds to the « second hit ». (figure 1) (3)


Figure 1: The genetic mechanisms that cause retinoblastoma

We can see here that in the hereditary RB, one of the parents has a mutated non-functional RB gene that is transmitted to the child. The remaining correct, or non-altered, copy is then inactivated by a random event (a mutation or an epigenetic event). The cell proliferation will then lead to the development of retinoblastoma.

In the non-hereditary form, the person has two normal copies of the gene. Two mutations are required for retinoblastoma to happen, which is rare.

In a normal individual, a cell can inactivate one of the two goods copies but this is not enough to lead to retinoblastoma.

Source: Molecular Biology of the Cell (6th edition) (3)

In the non-hereditary form, one cell inactivates one of its two RB genes. Later on, second hit will inactivate the second good copy of the RB gene, leading to retinoblastoma.

In the non-hereditary form, the person has two normal copies of the gene. Two mutations are required for retinoblastoma to happen, which is rare.

In a normal healthy individual, a cell can inactivate one of the two copies of its RB gene but as we described before, two mutations need to happen for someone to get retinoblastoma.

The occurrence of retinoblastoma both in the hereditary and non-hereditary RB is the result of multiple categories of mutations such as nonsense, frameshift, splice, missense or epigenetic mutations or even to a mutation in the promoter sequence of the gene.

The possible mutations are regrouped in the following table: (figure 2)

Figure 2 : Genes Mutations in the RB gene

The most frequent mutation is a substitution that leads to premature termination or splicing or missense. We can also have deletions mutations or less frequently, insertions.

Source : RB1 Gene Mutations in Retinoblastoma (4)

The majority of mutations identified in the hereditary form of RB are point nonsense mutations. They are distributed over the 27 exons or in the promoter sequence of the Rb gene. Most of the time there is a point mutation from a C nucleotide to a T nucleotide. A point mutation induces a premature stop codon. In this case, a CGA (Arginine) becomes a TGA (a stop codon). This premature arrest of the making pRB protein results in a shorter protein that may not function. (4).

Diagnostic/classification of the disease

The diagnostic of a child with suspected retinoblastoma is accomplished by some ocular examination, a test that allows the ophthalmologist to see inside the eye with an ophthalmoscope. An ultrasonography can also help to detect the mass of the tumor. The international system of classification of the retinoblastoma is based on the size of the tumor as well as on its localization. The type of retinoblastoma determines the treatment choice. There are several groups of disease: group A corresponds to a retinoblastoma tumor size of up to 3 mm, group B is for tumor bigger than 3 mm,  group C: retinoblastoma with localized seeds, group D: retinoblastoma with diffuse seeds and group E: retinoblastoma that needs enucleation, the removal of the eye (5).


Retinoblastoma has evolved throughout the years. Before it was a deadly childhood cancer, now currents treatments are evolving to provide the best vision possible to the patient.

There are several kinds of treatments for retinoblastoma (6).

Chemotherapy aims to reduce to a smaller size the tumor so that a laser treatment can then be effective. Laser treatment is generally for tumors that have been shrunk by chemotherapy. The laser is pointed on the dilated pupil using an indirect ophthalmoscope. There are two types of lasers ; one is a 532nM green light and the other is an 810nM infrared light. The second one is preferred to heat the tumor slowly. Cryotherapy is the use of a probe in the sclera of the eye. It produces low freezing temperature to kill the tumor. This is usually used for large peripheral or closed retina tumors. There is also radiotherapy, preferably, used when the tumor is not responsive to any treatments. It uses an external beam therapy or a radioactive plaque and can have important consequences such as other malignancies within the radiation field or dry eyes. Finally, enucleation, the oldest treatment of retinoblastoma, is curative for uniocular retinoblastoma or for the worse bilateral cases. It is reserved for extensive retinoblastoma where there is no hope to keep vision. The eye is removed and sends to histology to study the DNA sequence of the tumor (6). A prosthesis is then inserted to replace the shape of the eye.


Future treatment

Over the last few years, researchers tried to focus on developing new delivery chemotherapy methods with fewer side effects. For example, they develop techniques based on periocular injections of carboplatin and other agents in order to increase the efficacy of the drug used. One of the most promoting advances is the interventional radiological technique of intra-arterial chemotherapy (IAC). This technique allows the delivery of a chemotherapeutic agent directly into the ophthalmic artery, with few side effects. Current researches are directed towards gene therapy, stem cells and microarray technology to prevent tumor apparition.


 Retinoblastoma is a child tumor that can be genetic or non-genetic: it can affect one or both eyes. The most common symptoms are leukocoria and squint. Nowadays, multiple treatments exist as the choice of therapy depends on the tumor type whether the diagnosis is done early or not.


  1. Yannek I. Leiderman, Szilárd Kiss,Shizuo Mukai, Molecular Genetics of RB1—-The Retinoblastoma Gene, Seminars in Ophthalmology, 2007, 22:4, 247-254, Available from DOI: 10.1080/08820530701745165
  2. Milam A. Brantley, Jr. & J. William Harbour,The molecular biology of retinoblastoma, Ocular Immunology and Inflammation, 2001,9:1, 1-8, Available from DOI: 10.1076/ocii.
  3. Alberts B et al.Molecular Biology of the Cell.6’th ed. :Garland Science;2015.
  4. Dietmar R. Lohman, RB1 Gene Mutations in Retinoblastoma, Human Mutation, 1999,14 (4), 283-288, Available from DOI :https://doi.org/10.1002/(SICI)10981004(199910)14:4<283::AID-HUMU2>3.0.CO;2-J
  5. Parul Saxena, Jasbir Kaur, Differential expression of genes in retinoblastoma, Elsevier, 2010, 412 (23-24), 2015-2021, Available from DOI : https://doi.org/10.1016/j.cca.2010.10.009
  6. Manoj V. Parulekar, Retinoblastoma- Current treatment and future direction, Elsevier, 2010, 86 (10), 619-625, Available from DOI : https://doi.org/10.1016/j.earlhumdev.2010.08.022


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