What is retinoblastoma?
Retinoblastoma is the most common eye cancer in paediatrics, affecting mainly young children1. It represents 4% of all childhood malignancies2 and worldwide has an incidence of approximately 1 case per 16.000-18.000 live births, with the vast majority of cases occurring in Asia and Africa1. RB originates from the retina and grows in the direction of the vitreous humour and/or underneath the retina, producing retinal detachment. Without treatment, the natural trajectory of the disease is to grow from the retina both inside and outside of the eye. RB can spread to other structures of the eye, such as the choroid, the sclera and less frequently to the anterior chamber. At advanced stages, it can progress through the sclera to the orbit, through the ON to the brain, and also to the bone marrow.
However, with early detection and current treatments, RB is now a highly curable cancer. In developed countries such as Western Europe, the US and Canada, the disease-free survival (DFS) at 5 years of diagnosis is higher than 90%. That means that more than 90% of children diagnosed and treated in these countries will survive and be disease-free at 5 years after their diagnosis, and likely, disease-free for life. However, children with RB in other areas of the world, where the diagnosis is delayed and the resources for treatment are limited, the DFS at 5 years after diagnosis ranges from 70% to less than 30%1.
Retinoblastoma genetics and the importance of genetic counselling
When RB affects only one eye, it is called unilateral RB. When RB affects both eyes, it is called bilateral or hereditary RB. Approximately 75% of the cases are unilateral and 25% are bilateral3.
Most of the RB caused by mutations of the gene Rb1, which is a tumour-suppression gene. Tumour-suppression genes are genes meant to stop the over-proliferation of cells. We are all born with two copies of Rb1 (one inherited from our mother and the other one from our father), and a child needs both copies to be dysfunctional (mutated/deleted) in order to develop RB4,5.
Patients with bilateral disease are born with a germline mutation of the gene Rb1 (note: germline mutation means that you are born with a mutation of the gene Rb1 in all the cells of your body, including the retina). Being born with a germline abnormality in one of the two Rb1 genes increases the chances of developing RB in both eyes, as patients with one mutated Rb1 gene are vulnerable to develop RB in the event of a sporadic, or random, mutation in the other Rb1 gene cells of the retina. Twenty-five percent of patients with bilateral or hereditary retinoblastoma are born with a germline mutation that they inherited from one of their parents. The remaining 75% are born with a germline mutation that was formed by chance (de-novo) in the uterus, which means those patients didn’t inherit it from their parents, but all the cells in their body acquired that mutation during early fetal life3. Having a germline mutation (either inherited it from a parent or acquired de-novo), means that a patient can pass the genetic mutation to his/her offspring, who can potentially develop RB as well.
In addition, being born with a germline mutation of the gene Rb1 increases the chances of developing other tumours later in life. Because all the cells in the body are working with only one copy of the gene, another random mutation/deletion of the normal copy (among other genetic changes) may allow a new cancer to develop. These later mutations are strongly linked to the type and toxicities of the treatment for RB that patients received as children (see section 6).
Germline mutations of the gene Rb1, on the other hand, are rare in patients with unilateral RB, so they are called “sporadic retinoblastoma”. In fact, almost 90% of them are born without a germline mutation, which means that they only have a mutation of this gene in the retina cells, and that all the other cells of their bodies are normal. The remaining 10% of patients with unilateral RB are actually born with a germline mutation. Hence, only a genetic test can accurately rule out a germline mutation in patients with unilateral RB, even if a patient does not have a positive family history of it. In addition, a genetic test is the only way determine a patient’s chances of passing the mutation to the next generation3,6.
Now, let’s apply this new information to a few specific cases:
- Patient with a mother or father with RB: If a mother or a father with history of bilateral RB, or with unilateral RB and a known germline mutation, decides to father or mother children, they should know that their offspring will have a 45-50% chance of developing RB. Most of those children will have bilateral RB, but some may have unilateral RB.
- Parent with unilateral RB without family history: The child of a mother or a father with unilateral RB has around 5-7% chance of developing RB. This is an estimative figure since it implies that the genetic test has a 5% false negative rate, so even with a negative genetic test, there is still some higher risk of passing the disease to the offspring.
- None of the parents have the disease: RB patients born to parents without RB or without family history of RB are children that somehow develop a germline mutation in the uterus the affects all the cells in their bodies (and will likely have bilateral RB) or develop a mutation only in the cells of their retina (and will have unilateral RB). When both parents are genetically normal, the incidence of RB is extremely low.
However, it is also possible that one of the parents has the mutation and never had any manifestation of it. Such parents can still pass the mutation to their offspring. For example, it is possible that one of the parents had a benign tumour in the retina as a child, called retinoma, which “healed spontaneously” and never reach the point of developing into cancer. Most patients with retinoma also harbour a germline mutation of the gene Rb1 even if they never develop RB per se. In this situation, that parent can be considered a “carrier” of the mutation and even though this is a very rare, his or her children will have a 50% chance of inheriting the disease. Less commonly, a phenomenon called mosaicism occurs and not every cell of an individual carries the mutation, so in these rare cases, the inheritance of this tumour may not follow the above described rules.
In all cases, it is essential to emphasise the importance of adequate genetic counselling and testing for patients with RB (both bilateral or unilateral RB). Doing so helps determine the potential risk for the parents having another child with RB and the potential risk for the patient to eventually have a child with RB. Additionally, with counselling and testing, doctors can help to assess the real risk of the patient’s siblings developing the disease and can recommend screenings for those siblings.