Rb Fast Facts
Introduction to Rb
Global Incidence
Signs and Symptoms
Referral and Diagnosis
Staging Systems
Exam Under Anaesthetic
Treatment Options
Clinical Trials
Follow Up and Prognosis
RB1 Genetics
Glossary Of Terms
- the x and y chromosomes).
Each chromosome can be seen under a microscope, but genes can only be decoded using specialised techniques (DNA analysis or molecular genetics). Genes are copied during the constant process of cell division that causes us to grow, and mistakes can occur during that process.
The RB1 gene is found on chromosome 13. We all have two copies – one inherited from each parent. Retinoblastoma develops when both copies of the RB1 gene in a single retinal cell are damaged. Generically speaking, there are two different types of retinoblastoma – heritable and non-heritable. They are both caused by a mutation (error) on the RB1 gene.
In heritable retinoblastoma, a child either inherits one damaged copy of the RB1 gene from a parent, or damages or loses one copy very early in their own development. This means that all, or nearly all the cells in their body have one normal copy and one damaged copy of the RB1 gene. If any damage occurs to the normal copy in a retinal cell, a retinoblastoma will develop. This is why most children with heritable retinoblastoma develop multiple tumours in both eyes.
A heritable RB1 mutation may also be referred to by medical professionals as a "constirutional" or "germline" mutation.
Over 90% of children who carry a heritable RB1 mutation will develop retinoblastoma. Most will develop a number of tumours in both eyes. Some will have more than one tumour but only in one eye, and a few will develop only one tumour in one eye. A small number of children will not develop retinoblastoma, because the normal copy of RB1 does not become damaged in any retinal cell.
All cases of bilateral retinoblastoma are heritable, and approximately 17% of children with unilateral retinoblastoma have a heritable RB1 mutation. Multifocal retinoblastoma is an indicator of a heritable RB1 mutation in unilateral patients, though it is clinically difficult to differentiate between true multifocal tumours and seeds – pieces of tumour that have broken away from the original single mass.
When a child has unilateral retinoblastoma with no family history, precise molecular genetic testing is the only reliable way to determine their risk for heritable retinoblastoma.
Carriers of a heritable RB1 mutation have a 50/50 chance of passing the mutated RB1 gene to their children, but only 10% of heritable mutations are actually inherited from a parent. In most cases, the RB1 mutation occurs spontaneously at or after conception. When the mutation happens after conception, the child will have a mosaic mutation.
Mosaicism means that only a fraction of cells in the whole body carry one mutated copy of the RB1 gene. Each of these cells also carries one normal copy of the RB1 gene. The remaining cells carry two normal copies of the RB1 gene. Mosaicism only ever happens at or after the point of conception, so it cannot be inherited.
Imagine a two cell embryo. Each of the two cells has two healthy copies of the RB1 gene. In the process of normal cell division, one copy of the RB1 gene in one of those two cells somehow becomes damaged. Now there are four cells, but one of them carries a mutated copy of the RB1 gene. Those four cells then divide to become eight cells, two of which carry a mutated copy of the RB1 gene. And so on and so on.
When the baby is born, 25% of his cells will carry a mutated copy of the RB1 gene and one normal copy of the RB1 gene. The other 75% of cells will carry two normal copies of RB1. In order for retinoblastoma to develop, the healthy copy of the RB1 gene must also become mutated in a retinal cell where one copy of the RB1 gene is already damaged.
Mosaicism occurs in about 10% of heritable RB1 mutations, and can affect both boys and girls in equal measure. Theoretically, the lower the penetration of the mosaicism (the lower the fraction of affected cells), the lower the chances of developing tumours, but the chance is still there.
If a child is shown through genetic testing to be mosaic for the RB1 mutation, this is very useful to the family, since mosaicism cannot be inherited. This means parents, siblings and other blood relatives are not at risk. However, children born to a carrier of a mosaic RB1 mutation will be at risk for inheriting the RB1 mutation from their parent. If this happens, one copy of RB1 will be mutated in every cell of their body.
If genetic testing identifies a heritable mutation that is not mosaic, DNA or molecular genetic testing can be used to establish risk for parents, siblings and other blood relatives. In order to determine risk for an unaffected blood relative, the mutation must first be identified in the child who is already diagnosed with retinoblastoma. Testing cannot be done directly on unaffected blood relatives.
If an unaffected sibling is found to not carry the heritable RB1 mutation identified in their brother or sister who has retinoblastoma, they will not need to undergo repeated screening under general anaesthetic. Genetic testing of unborn at risk siblings can be done through amniocentesis or CVS, or at birth from a cord blood sample.
Health economists estimate that precise molecular genetic testing is 75% less costly for retinoblastoma families than years of conventional screening for unaffected siblings of a child with retinoblastoma. However, this testing is expensive and technically difficult, as the RB1 gene is large. Mutations can happen anywhere on the gene, and are often unique to individual families.
Very precise testing for mosaicism is currently available only in Toronto (Canada), Essen (Germany) and Paris (France). If testing at one of these three laboratories fails to find a heritable mutation in a bilateral child, this will be because the child has a mosaic mutation in such a low fraction of cells that it cannot be detected with current technologies. Such a result determines that the child’s parents and siblings are not at risk.
If testing at one of these three labs is unable to find a mutation in blood for a unilateral child with no family history of retinoblastoma, this reduces the child's risk of an undetectable mosaic mutation to approximately 1%. This means that unaffected siblings are not at risk. It also means that, on condition of the health of the affected eye, the child can be followed with awake examinations in clinic, as the chance of new tumours developing in the remaining eye is minimal.
Although there are a number of additional laboratories around the world which test for RB1 mutations, they are not able to accurately test for unilateral retinoblastoma with no family history. This is because they cannot test accurately for mosaic mutations.
When an RB1 mutation is identified, the affected child should receive eye examinations immediately to ensure that any tumour growth is diagnosed and treated as early as possible. For specific details on recommended examination schedule, click here.
Carriers of a heritable RB1 mutation also have an increased risk of developing other tumours, away from the eye, later in life. They should therefore be closely followed throughout life by an oncologist. The mechanism for development of these other tumours is the same as for retinoblastoma, .e. the normal copy of the RB1 gene must also become damaged. Other genes may also be involved in the formation of these cancers. Second Primary Tumours usually affect the bones, soft tissue, muscles, skin or brain.
Survivors of unilateral retinoblastoma who do not carry a heritable RB1 mutation do not have any further cancer risk above that of the normal population.
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