Mixing metaphors at the molecular level – understanding genetic test results

So there were results, Alison?

Yes, there were results! I received a letter from my genetics consultant to go and see him on Friday 11 April with a view to discussing the results of genetic testing of material from my Vestibular Schwannoma and 2003 spinal schwannoma. The material got sent away to the National Genetics Laboratory in Manchester. They were going to use their extensive collection of machines that go ‘ping!’ to find out if those two troublesome tumours were linked, in particular whether they were the result of my having a mosaic form of Neurofibromatosis Type 2 (‘NF2’).

Here comes the metaphorical part!

NF2 is a gene that encodes for (i.e. contains the genetic information for) the production of Merlin (a.k.a. Schwannomin), a cytoskeletal protein that has a tumour suppressor function in humans. So, DNA is basically a recipe book, and the NF2 gene is a recipe to make ‘Merlin’- let’s think of it as protein-cake. Most people have two NF2 ‘alleles’, that is to say that the DNA recipe book contains two copies of the NF2 recipe just in case you manage to cover one version in the genetic equivalent of bolognese sauce and it becomes unreadable. That’s OK – just like a recipe book one full version of the recipe is quite sufficient to make as much Merlin protein-cake as you need. The problem comes when something has happened to mess up both your copies of the recipe.

So there are a number of different things that could happen to your NF2 genes to mess them up. With their recipe metaphor equivalents, they are:

One of your copies of the NF2 gene is missing. In metaphor terms, there is a page missing out of your recipe book, and it is one of the pages with an NF2 recipe on it. I believe that the technical term for this is ‘Loss of Heterozygosity’ (‘LoH’), ‘a gross chromosomal event that results in loss of the entire gene and the surrounding chromosomal region’ according to Wikipedia. Yes, as I said, missing page.

One of your copies of the NF2 gene has mutated and part of it has been deleted. In recipe terms, this could be missing ingredients or missing instructions.

One of your copies of the NF2 gene has mutated and something extra has been inserted. In recipe terms, this could be extra ingredients or additional instructions.

Where the thing that has been deleted or inserted is a single base pair (i.e the building blocks of DNA usually represented bu the letters C,T,A or G) this is often known as a ‘point mutation’.

Still with me?

Genetic mutations can have a variety of consequences.

Nonsense mutations occur where (point) insertions or deletions lead to a change in the genetic instructions resulting in a premature ‘stop codon’. This leads to production of a shortened protein which may function poorly or not at all. Cookbook equivalent? There has been a misprint of your NF2 recipe and the last two or three instructions, including the bit where you put the cake mix in the oven, have been left off so you get left with gloop rather than protein-cake.

Missense mutations occur where (point) insertions or deletions lead to a change in the genetic instructions resulting in a different amino acid being produced at that part of the protein, which may or may not affect it’s function. So imagine our NF2 recipe made some sort of protein fruitcake. The mutation might be the equivalent of missing the instruction for flaked almonds or putting an extra 25 grammes of chopped glace cherries in, in which case it wasn’t quite what you thought you were making but you still end up with a cake. Or it might be an extra 2 tablespooons of salt added to the ingredients list, so it will look like a cake but in fact be inedible.

OK. So now you have a grasp of the fundamentals of genetic mutations. If my explanations have left you confused and not wanting to go into the kitchen any more, you can find better explanations and examples here: http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/possiblemutations . Extending our metaphor, that is like the online genetic mutation equivalent of Delia Smith’s ‘How to Cook’.

So how do we get from there to determining if a person has mosaic NF2?

Well, the NF2 gene is biallelically inactivated in schwannomas. That is to say that in the tumour tissue both your copies of the recipe are either missing or faulty and not able to produce Merlin protein-cake. If you have full NF2 then you can find out exactly what types of mutation there have been to the NF2 gene from a blood sample. If you have a mosaic form of NF2, then not all of your cells contain two faulty NF2 recipes so typically you cannot detect it from a sample of blood, but all of your NF2-related tumours will contain the same two faults.

So the testing at the lab in Manchester first tries to determine what has happened to each of my two copies of the NF2 gene in the vestibular schwannoma, and then looks to see if the same two faults can be found in my spinal schwannoma sample.

In the vestibular schwannoma they find one totally missing recipe (that’s LoH as described above) and a chunk of missing instructions in the other (a point deletion leading to a premature stop codon).

In the spinal schwannoma they find the same totally missing copy of the recipe but (to use the now very tired metaphor) the recipe book has been so badly looked after and is in such a poor state of repair that they cannot identify the same chunk of missing instructions in the mass of recipe scraps that remain.

And where does this leave me?

Pretty much where I was before the appointment, if I am honest. Which is to say i) feeling that I may be more prone to these kinds of growths than the average person, but ii) having no scientific evidence to back up that feeling.

A definite result one way or the other was never going to dramatically change my life – it would only have formalised the processes of keeping a careful eye out for signs of further tumours which I would have done anyway, having already had two that have been rather inconvenient to say that least. However, if at some point in the future I should find myself with another you can be sure that I will make certain that any tumour tissue is more carefully preserved and more quickly tested!

In other news – February’s MRI scan results are in 

Letter from the consultant dated 18 March confirms that: ‘The scan shows that there is only a very tiny amount of residual enhancing material where your previous tumour was. This may indeed just be some scar tissue.’ My health team will take another look in 12 months’ time.

Finally…….

Things have felt a little grim around here of late. So much health-related information, so little of the food and dogs that I promised in my strap-line. Next time I get around to posting it will definitely be about the hounds. They are not well trained. But I have this book called ‘Total Recall’ and an ‘Acme Gundog 210’ whistle and everything is going to change around here……..