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genetics:interpretation:phase [Retinoblastoma Wiki]
 

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Question regarding the phase of two mutations

Sporadic unilateral or bilateral RB, 2 small mutations in the tumor (eg 2 nonsense mutations) , none found in the germline of the patient. No indication wether these mutations are in cis or trans. Would you assume the mutations are in trans and threrfore cancel eye exam in siblings? or stay cautious in maintaining exam?

Opinion 1

we have several of these cases and I assume trans. I would only doubt trans if the two mutations are located very near to each other and a unique complex mt might have caused both alterations.

My ad hoc argumentation is based on probability (i.e. statistical) and goes as follows:

  1. I do not remember a somatic “passenger” or “bystander” alteration in addition to a bona fide oncogenic mutation.
  2. 2. Any random substition (that is a potential bystander) that we might pick up by screening RB1 sequence will result (with decreasing probability as estimated without looking into the literature) in neutral intron change > missense change > neutral exon change > splice intron change > nonsense
  3. So, if “passenger” or “bystander” alterations occur with appreciable frequency then I would expect to find foremost neutral intron changes. Nonsense mts are not the changes that I would expect to see if there is no selection based on loss of function (as is with RB1 inactivation).

There is, however, a caveat and this is multifocality. So if you inadvertently have DNA from two foci you might find two mutations and still one missing.

Opinion 2

We also assume that if we find two heterozygous small RB1 mutations (e.g. nonsense) in a unilateral (sporadic) tumor that they are in trans. Therefore, for a unilateral patient, if we found neither tumor mutation in blood, then we would report that the retinoblastoma was highly likely not to have been inherited, and that sibs would not be at increased risk. We have had the rare case where the two observed somatic changes were near to each other and we were not sure whether they were two separate events or part of the same event . (We have never seen the situation where we had two somatic mutations in tumor in a bilateral and neither in blood. In a few cases one of the tumor mutations is at a very low level in blood (e.g. 10%), and in some cases we can only see the bilateral mutation in blood by Allele Specific PCR and not by sequence. I would really want to see some evidence of one of the tumor mutations in blood in a bilateral).

The above argument has merit. We also have not seen a somatic “bystander” change in addition to an oncogenic mutation in tumor. In particular, we have never seen a neutral RB1 exon change as a random somatic event in tumor, (>300 uni tumor samples analyzed)and one might expect to see this more commonly than nonsense under conditions (i.e. in cis) where there is no selection based on loss of function.

Another way of thinking about it::

  1. If the first somatic mutation occurs in one cell (perhaps becomes a small group of cells), and then by chance a second mutation occurs in cis with the first mutation, then a third mutation would still have to occur in trans in the SAME cell to initiate the tumor and the chance of three RB1 somatic mutations occurring in one cell would be far smaller than the probability of two somatic mutations, hence would be very unlikely.
  2. If on the other hand the second mutation occurs trans and a tumor is initiated , then a third mutation occurs cis to one of the two mutations in one of the tumor cells, then the cis mutation would only be present in a fraction of the tumor cells.

In case it is helpful: we do have three cases in our database (all non-germline) where there is evidence of multifocality. In two cases we see only one copy of P-27 and two heterozygous “small” mutationxs (e.g. nonsense). In the other case we see two thirds or more of the DNA with a nonsense mutation and 1/3 or less with a small deletion suggesting a mix of a clone with a homozygous nonsense and a clone with the same hetero nonsense and a hetero small deletion.

 
genetics/interpretation/phase.txt · Last modified: 2007/06/03 18:02 by dietmar
 
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