RB genetics ... What would happen in Ethiopia?

Retinoblastoma is a complicated business. It’s not uncommon for us to ask a question of a doctor, only to be told, "Ah, that's a question for Dr X."

The team that manages Asa’s treatment includes ophthalmologists, oncologists, and geneticists – each of whom contributes a piece of the puzzle.

As it turns out, some of our questions about the causes of Rb and its long-term implications are questions for geneticists.

Genetics is relevant here because, given that both Asa's eyes are affected, there's a very high likelihood that it’s due to a mutation in a gene known as RB1. 

Dr Rosser, a geneticist at Great Ormond Street Hospital, helped us understand how this mutation might have arisen, and what its implications are.

Since neither Selam nor I have relatives with Rb, the most likely way Asa got the mutation is through a random change in the sperm or egg that made him.

As Dr Rosser explained: "Every time a cell divides, 40,000 genes get copied.”

“All of us have 20-50 mistakes in every gene, but most don’t matter.

“His matters."

It’s kind of a relief to know that genetic mutations are common – that we all have them.  And that they’re not always bad news.

But obviously some are more important than others.

How does Asa’s matter? 

How (not) to build a retina

One of the major jobs genes do is to give instructions on how to build a body.  Genes have relatively specialised tasks, and the job of the RB gene is to issue the command, "Stop growing, retina." When there's a mutation in this gene, the "stop" command doesn’t register, and cells keep dividing in the retina area, more than are needed. (Retinoblastoma literally means growth on the retina – blastos being Greek for bud or growth.)

Eye anatomy, showing the retina (from visionandeyecare.wordpress.com)

Since the retina does most of its developing by age 5 – and most of that during the first two and a half years – Asa will be at greatest risk from Rb during the first 5 years of his life.  After that, according to Dr Rosser, he will have about a 6% chance of other tumours, e.g. in bones, muscle or skin, with the risk peaking in his teens or early 20s, and declining thereafter.

There are two other corollaries of RB mutation: it may be accompanied by other mutations, and it can be passed on to children.

 

Sometimes when the RB gene isn’t working, it’s the first sign that there are other abnormalities: neighbouring genes could also be faulty, and these could lead to other problems in development.  We will have to keep an eye out for developmental oddities in Asa.  The fact that he’s developing normally so far (he started walking independently this week!) bodes well.

There’s a 50:50 chance that Asa’s children might inherit the RB mutation.  Knowing this, however, means that any child he might have could receive prompt evaluation and, if necessary, treatment to nip tumours in the bud.

How common is Rb?

For some reason, the copying mistake that leads to the RB mutation happens at a fairly predictable rate across human populations.  The figure that's often cited is 1 in 20,000 (50 in a million). 

The universality of this phenomenon can be difficult to believe, because almost everything you see on the internet (and we’ve spent some months searching) is related to Rb in Europe and North America.

In Europe, we learned recently, there’s some variation, with slightly higher incidence rates in the north than the south (MacCarthy et al. 2006).

But if it occurs at roughly the same rate all over the world, how come we don’t hear more about Rb in Asia, Africa, and South America?  

Some possible answers are that high child mortality from infectious diseases in the developing world makes cancer a marginal concern; there are a lot more resources available for cancer treatment in the West; and the internet is Eurocentric.

Still, we wonder.  Are there really thousands of children born with Rb in the developing world?  What happens to them?

What would Asa’s chances of survival have been if he was in Ethiopia?

Rb worldwide

This month, a review was published in the Lancet by a team of physicians in Canada and Kenya (Dimaras et al. 2012).

Their review doesn’t confirm the 1 in 20,000 incidence rate, but it does show that there’s a lot of Rb in other parts of the world.

In Kenya (one of the few countries in Africa where there is a dedicated treatment centre for Rb) more than 70% of children with Rb die from it. The mortality rate from Rb is surely higher in places where there are no treatment centres.

What happens when Rb goes untreated is quite horrific.  The Lancet article includes a photograph of a child with a very large tumour that has burst out of the eye socket.

Ethiopia is one of the places that lacks a treatment centre.  While we don’t know how many children in Ethiopia have Rb, the ophthalmologist in Addis Ababa who first diagnosed Asa, had referred patients to Kenya. 

And as the second most populous country in Africa, Ethiopia usually comes close to the top of the list when cases of disease are tallied up.

So given what we know about the genetic basis of Rb, and its regular incidence rate, it seems likely that there are scores of children being born with Rb in Ethiopia, most of whom will die of it.

Selam and I would like to help families there whose children have Rb get treatment. Next week I’m going to Ethiopia, and I’ll try to find out more about how we might do this. 

Sources:

A recent article documents the commonness of genetic mutations, and suggests that most do not have any major consequences for health (MacArthur et al. 2012, Science 335, 6070:823-8; news item here). 

 

Incidence of retinoblastoma higher in northern than southern Europe (MacCarthy et al.2006, European Journal of Cancer 42, 13: 2092–2102)

Lancet review of retinoblastoma (Dimaras et al. 2012, Lancet 2012, doi:10.1016/S0140-6736(11)61137-9)

Thanks to Charlotte Kvasnovsky for letting us know about the Lancet review.