Wednesday, July 25, 2012

13q Part Three - interpreting test results and understanding limitations

13q test results:

When FISH is ordered and a 13q abnormality is observed, there are a variety of ways it can be reported.  It is possible to have a deletion on one chromosome in many of the cells, a deletion on both chromosomes in some of the cells, or any combination of the two.  Typically the report will indicate the number of cells lacking one or both copies of 13q.

Up until recently, we were not totally clear how these differences influenced clinical outcome.  Several earlier papers seemed to indicate that having both copies of 13q missing was worse than having only one copy missing.  Unfortunately, some of these studies were limited by small sample sizes and may not have statistically accurately reflected what these results mean.

Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays.

Biallelic deletion 13q14.3 in patients with chronic lymphocytic leukemia: cytogenetic, FISH and clinical studies.

More recently, several groups seem to have arrived at consensus that the actual percentage of cells lacking the 13q matters more than whether there is only one copy or two.  Different groups come up with different number thresholds, but that is because they need to make a categorical separation of data that is by nature a continuous variable.  It is probably safe to say that the more cells with 13q deletions the worse it is.

There are a number of things however that FISH simply doesn't tells us.  In some cases we know whether the missing data is important, in some cases, we have yet to figure it out.  FISH does not distinguish between the minimal deleted region (MDR), commonly deleted region (CDR) which contain Dleu7, or the less frequent larger 13q deletions that contain the RB protein (type II deletion).  Unfortunately FISH only tells us if there is a deletion or not - it doesn't tell us the size or what genes are included.

Mutations have been found in the Rb protein in patients with CLL, but those are not detectable by FISH.  Other conditions where the cell tries to replace the missing material by making an extra copy of the remaining chromosome (aka uniparental disomy) are missed entirely.  Furthermore, the cancer cell can turn off the mRNA's through a process called methylation and even if you could figure all this out, it is not clear how these findings affect the biology.

For now we know that if you have a 13q deletion and NO OTHER FISH abnormalities, you are probably in good shape.  If you also have a 17p or 11q, those trump the 13q.  Hopefully we will learn how to handle the other information we know is there and create tests that let us sort it all out.