Dr Simon Ramsden and Dr Trevor Cole answer some of the most frequently asked questions about genetic testing in retinoblastoma…

Why do we carry out genetic testing for retinoblastoma?

Genetic testing is predominantly used to advise on the recurrence risks to relatives of an affected child. Blood relatives who are at risk of the disease must be closely followed with regular eye examinations up until the age of five, so that if tumours form they are discovered and treated as early as possible.

In young children who are unable to cooperate fully with eye examinations, this procedure is performed under general anaesthetic and requires frequent visits to hospital.

What puts a family member at risk?

To understand this you need to understand a bit about the genetic mechanism underlying retinoblastoma.

Retinoblastoma is caused by errors (mutations) in the RB1 gene. You have two copies of this gene in each cell (one from your mother and one from your father).

Retinoblastoma occurs when both copies of the gene are damaged in a single retinal cell. When this happens, one of the important controls (“brakes”) of cell growth and division is lost and, as a result, tumours can form.

Retinoblastoma occurs in two forms: the heritable (or genetic) form and the non-heritable (or non-genetic) form.

This distinction is used to help identify two groups of patients – those where family members are at risk of developing retinoblastoma (heritable) and those where family members are not at risk of developing it (non-heritable).

In practice this can be a difficult distinction to make and risks to family members can sometimes not be established unequivocally.

There are four possible scenarios:

  1. When an RB1 mutation has been inherited from a parent (who may or may not be affected but does carry the RB1 mutation in at least some of their cells) retinoblastoma develops in a child when a second mutation arises by chance in a retinal cell. In this case, the tumours are usually bilateral, and both the brothers and sisters, and future children of the affected child, will be at risk.
  1. When a new RB1 mutation occurs for the first time in the sperm or egg of the parent of an affected child. In this case the RB1 gene mutation will not be present in other cells in the parent. However the mutation will have been inherited by the child and retinoblastoma develops when a second mutation arises by chance in a retinal cell. These patients also usually have bilateral disease and their future children will be at risk of developing retinoblastoma (but their brothers and sisters will be at low risk).
  1. If the first RB1 mutation occurs by chance in a developing retinal cell of a healthy individual, then a second mutation may occur – again by chance and the tumour will develop in one eye (unilateral disease). In this case, the patient’s brothers and sisters (and in the long term the patient’s own children) are at low risk of developing retinoblastoma. This is a non-heritable form of retinoblastoma.
  1. If the first mutation in the RB1 gene arises during early embryological development there is a risk that the mutation will be present in a group (or “sub-set”) of the cells in the body including the retinal cells. A tumour may develop on occurrence of a second mutation in one or both eyes respectively. Brothers and sisters of these patients are at low risk of developing retinoblastoma. However, when the affected patients have children of their own they may be at risk of passing on the mutation, depending on whether these cells were part of the group affected by the original mutation. As these patients can have either bilateral or unilateral disease this makes risk prediction very difficult. So this form of retinoblastoma could be either heritable or non-heritable.

In practice it is often difficult to distinguish between these four scenarios and management of patients and their relatives is cautious, assuming family members are at risk until we have good clinical and laboratory evidence to the contrary.

The genetic counsellor will discuss any possible family history of the disease and guide the family through the testing options aimed primarily at identifying the first causative RB1 mutation in an affected child.

When a mutation is found, we can test family members in an attempt to offer reassurance and to exclude the need for examinations under anaesthetic for as many relatives as possible. Children with confirmed or possible heritable retinoblastoma will be offered genetic counselling when they are old enough to understand it.

Molecular genetic testing for RB1 gene mutations is a complex task, requiring expertise and technology available in only a few laboratories which specialise in retinoblastoma.

How do I arrange genetic counselling?

If you have any 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 your own family or personal circumstances.

If you’re not currently attending the retinoblastoma treatment centres in London or Birmingham and wish to have genetic counselling, there are a number of options:

  • Contact your GP and ask to be referred to a local genetics counsellor who will make arrangements for you.
  • Contact a CHECT support worker who will put you in contact with the right people at either Rb centre (Royal London Hospital or Birmingham Children’s Hospital).
  • Contact either Rb centre direct and ask to be put in touch with their specialist genetic counselling professionals.

About the authors

Dr Simon Ramsden, Consultant Clinical Scientist, Manchester Centre for Genomic Medicine, Genomic Diagnostics Laboratory, 6th Floor St Mary’s Hospital, Oxford Road, Manchester M13 OJH.

Dr Trevor Cole, Consultant and Honorary Reader in Clinical and Cancer Genetics, Birmingham Women’s NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG.

This article first appeared in the Winter 2014 edition of InFocus. Find out more about the genetics of retinoblastoma