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Childhood Eye Cancer Trust - genetic testing
Childhood Eye Cancer Trust - genetic testing
Childhood Eye Cancer Trust - genetic testing

This information was written by Megan Pritchard and reviewed by Dr Elisabeth Rosser, consultant geneticist at RLH and Dr Gerald Draper, consultant geneticist (retired) at BCH.

What are genes?
Genes are instructions that control the way we grow and develop. We all have many thousands of genes, each of which does something different. We have two copies of nearly every gene, inheriting one copy from each parent. All our genes can be found within each cell of our body. The genes are copied every time a cell divides; this means that every gene is copied many millions of times during our lifetime. The genes are also copied many times when egg or sperm cells are made. Not surprisingly copying mistakes can occur at any of these stages. We all have about 20 genes that have a copying mistake in them; the majority of these do not have any effect and so we are not aware of them. Some copying mistakes or alterations are inherited from one of our parents, others start in us.

What are chromosomes?
The many genes are packaged together; the gene packages are called chromosomes. There are 23 pairs of chromosomes; each chromosome can be seen through a microscope but genes can only be decoded using specialised techniques (DNA analysis or molecular genetics).

What does the gene for retinoblastoma (Rb) do?
The retinoblastoma (Rb) gene is found on chromosome 13. (It is usually called the RB1 gene in scientific literature.) As with nearly all our genes we have two copies of it. It is quite a large gene with 27 different sections. The information it provides allows our bodies to make a substance called a protein, which is then able to carry out a specific function in our bodies and within the cell itself. The protein produced by the retinoblastoma gene plays an important role in ensuring healthy cell division as we grow and develop.

All cells have a life cycle. An important part of that is the period during which the cell replicates and divides. During this process, all the genes within a cell must also be copied so the new cell has all the information it needs to function properly. Certain proteins, such as the one produced by the retinoblastoma gene, perform checks at stages throughout the copying and dividing process to ensure that the cells are dividing correctly and the new cells are healthy, without alterations in the genetic material. If it detects changes, the protein is able to halt the dividing process while repairs are made, so preventing these altered and therefore damaged cells from continuing to grow and divide.

How does retinoblastoma develop?
In the first few years of life the retina grows very quickly; this means that our cells must divide quickly. At this fast pace, mistakes are more likely to occur as our genes are copied. As a result of these alterations a retinoblastoma can occur; this can happen in either of two different ways:

• When a child inherits one altered copy of the Rb gene from a parent. If the normal copy of the gene does not become damaged in a retinal cell no retinoblastoma will develop. If damage occurs to the normal copy, a retinoblastoma can develop. This is the heritable form of Rb. About 90% of people who inherit an altered Rb gene from a parent will develop Rb; most will have bilateral disease (i.e. both eyes affected), a few will have multifocal disease (more than one tumour in an eye), and a few will have unilateral disease (one eye affected) with only one tumour. About 10% will not develop a tumour at all. In heritable Rb all the cells in the body, including the blood cells, will contain the altered copy.
• When a child inherits one normal copy of the Rb gene from each parent but copying mistakes then affect both copies of the gene in one cell of the retina. Again, as a result of these alterations a retinoblastoma can develop. In these circumstances the child will develop the non-heritable type of Rb, and there will be one tumour in one eye only.

Bilateral, multifocal and unilateral types of retinoblastoma
A person with bilateral or multifocal retinoblastoma (Rb) has the heritable form: the altered gene is present in all of their cells. For (some of) their blood relatives there is also an increased chance of retinoblastoma occurring.

The situation for people with unilateral Rb is more complicated. In 80-85% of unilateral cases most cells in the body will not have the altered gene, and there is a no increased chance of retinoblastoma occurring again or in their families. However, around 15-20% will have the heritable form. Some may have a family history of the disease. It is not always possible to tell whether a particular patient is in the heritable or the non-heritable group. See screening your child for more information.

Very rare forms of Rb: What is chromosome 13q deletion?
About 5% of people with retinoblastoma (Rb) have lost the part of chromosome 13 that contains the Rb gene. They have what is called chromosome 13q deletion.

From a retinoblastoma point of view they have heritable Rb. In cases of chromosome 13q deletion other genes may also be lost or damaged and this may cause some physical or developmental delays or disabilities. The amount of genetic information lost varies from person to person.

When can genetic tests be useful?
The value of genetic tests depends on the type of retinoblastoma and the family history.

If retinoblastoma is newly diagnosed in a family, parents are encouraged to have an eye examination. This examination is to check for signs of a tumour that may have gone undetected and never caused any symptoms. Such tumours have been ‘inactivated’ in some way, probably by the body’s own immune system. Although this situation is very unusual, it is important to check for it, as it means that the parent carries an alteration in their Rb gene, and there is a chance that future children may inherit the altered gene and be at risk of developing retinoblastoma. A brother or sister or a child of someone with retinoblastoma (Rb) should have regular eye examinations until they are 5 unless genetic testing shows that it is not needed for a particular child. Read our page on screening for retinoblastoma.

Genetic testing can be useful:
• To inform a newly diagnosed person, and their family, of their genetic status.
• To clarify the chances of other children having Rb. If it can show that a child has not inherited an altered gene, they will not need to be examined under anaesthetic.
• To clarify the situation for unaffected people in families where other members are affected by retinoblastoma (Rb).
• To test a pregnancy to know whether the foetus has a chance of developing Rb. This can only be offered if prior testing has identified the gene alteration.

What laboratory tests can be done?
The tests done in retinoblastoma can be divided into three groups:
1. Chromosome analysis to look for a visible change in chromosome 13. This is likely to be normal in 95% of cases and show a deletion (missing piece) in 5% of cases.
2. DNA or molecular genetic testing to look for the alteration or damage in the Rb gene in the affected person. This testing is technically difficult, as the Rb gene is quite large and alterations can happen anywhere in it. The location of the alteration tends to be different in different families; so the testing can take many months. It is carried out primarily by the Retinoblastoma Genetic Screening Unit at Bart’s and The London NHS Trust and The Genetics Screening Unit at St Mary’s Hospital in Manchester. The tests are not sensitive enough yet to pick up every alteration in the gene, although about 90% of altered genes can usually be found.
3. DNA or molecular genetic testing to compare the Rb genes in the family to find out which is the altered copy of the gene without actually finding out what the alteration is. This is also called linkage analysis. It can be done only if there are at least two people with Rb in the family.

What will genetic testing show?
Testing blood samples: For people with bilateral or multifocal Rb, alterations in the Rb gene can usually be identified using blood samples.

For those with unilateral Rb, genetic testing may help to clarify which group someone is in, i.e. heritable or non-heritable. If an alteration is found in the Rb gene in blood cells this will confirm that the person has the heritable form. If an alteration is not found this may be because no alteration is present or because tests have failed to detect an alteration and therefore the results at this stage may be inconclusive.

If an alteration cannot be found in the Rb gene in the blood cells, it may be possible for further tests to be done by examining a sample of the tumour if an eye has been removed.

Testing tumour tissue samples: Looking at the Rb gene in tumour tissue is useful both in people with bilateral Rb whose blood test has been negative and in people with unilateral Rb. This is because if alterations are found in the Rb gene in the tumour then it shows exactly what to look for in the blood, and if these alterations are not detected in the blood then it is certain that there are no alterations in the blood. In these cases it can be concluded that the Rb is non-heritable, rather than that the tests have failed to find the changes.

What is genetic counselling?
The Association of Genetic Nurses and Counsellors, the regulatory body in the UK describes the aims of genetic counselling in this way.

To help the individual or family:
• understand information about the genetic condition
• appreciate the inheritance pattern and risk of recurrence
• understand the options available
• make decisions appropriate to their personal and family situation
• make the best possible adjustment to the disorder or risk.

For families or individuals with questions and concerns about retinoblastoma or genetic testing, genetic counselling can offer not only technical information but also some assistance in understanding the information in relation to their own family or personal circumstances.

Have you been affected by retinoblastoma?
If you are not currently attending one of the retinoblastoma treatment centres in London or Birmingham and wish to have genetic counselling, please contact your GP and ask to be referred to a local genetics counsellor who will make arrangements for you. Alternatively you can contact either retinoblastoma centre and ask to be put in contact with their specialist genetic counselling professionals.

See also

Childhood Eye Cancer Trust - Screening


Childhood Eye Cancer Trust - Your Support Worker


Childhood Eye Cancer Trust - Fundraise