Saturday, October 16, 2010

the 14 queue

At the long end of chromosome 14 is the little gene mechanism that protects us from infection. It is a very complex sequence of genes that generates the diversity necessary to make antibodies. There are millions of germs out there and the body needs to react rapidly to produce a defence against them. It does so by already having the templates ready to go for any possible germ. There are a few hundred components that can be mixed and matched and assembled in an appropriate way, and when they are put together properly there is another 'promoter' gene that ensures that the antibody is made in huge quantities.

I call the promoter gene the 'make a lot of' gene, and normally it makes a lot of antibody. The trouble with this area on the long arm of chromosome 14 is that because of all that mixing and matching going on, very occasionally the chromosomes mix inappropriately and the 'make a lot of' gene gets stuck somewhere it shouldn't causing the cell to make a lot of the wrong stuff. It can even get stuck next to a gene on a different chromosome. Such events are called translocations and they often result in lymphomas.

For example in the t(8;14) translocation the 'make a lot gene of' is put next to c-myc and you end up with Burkitt'slymphoma; in the t(11;14) translocation it is put next to CCND1 and you get mantle cell lymphoma; in the t(14:18) translocation it is put next to bcl-2 and you get follicular lymphoma and in the t(14;19) translocation it is put next to bcl-3 and you get a rather atypical form of CLL.

Sometimes, however, the end of chromosome 14 is missing and no-one knows where it has gone. It does not turn up partnering another chromosome. This topic is discussed in the October Brit J Haem in an article by Reindl from Munich.

They have looked at 3054 patients with mature B cell neoplasms and identified 47 cases with deletion at the end of 14q (the long end of the chromosome is called 'q' and the short end is called 'p'). 35 of the cases had CLL/SLL, 10 had CLL/PLL and one had lymphoplasmacytic lymphoma and one marginal zone lymphoma. (NB: this is a biased sample; only about 18% of chromosomal specimens with del 14q come from CLL patients according to the Mitelman database.) This tells us that del 14q is rare in CLL at 1.9%, but significantly commoner in CLL/PLL at 9%.

Despite careful searches for translocations, there was no corresponing partner chromosome to which the broken off piece had been moved; these were all true deletions - a bit of the chromosome had been lost. The exact amount of the chromosome that was lost was variable, and two thirds a timy bit had been left at the end. There were three broad patterns, but some variation, even with these.

80% of the cases had extra chromosomal abnormalities, - most commonly trisomy 12. There were 17 cases with very complex chromosomal abnormalities and these tended to have del 17p, as you might expect, since loss of TP53 function does lead to that. There were significantly more patients with del 14q among those with unmutated IGHV genes - again not unexpected.

Compared with other cases of CLL or CLL/PLL, having a 14q deletion did not impact of the 3-year overall survival, but the time to first treatment was much shorter at 21 months vs 80.1 months. However, compared to patients who had trisomy 12 without del 14q, those who had the extra deletion had a significantly shorter time to first treatment and overall survival.

So, does this paper tell us much? Not yet. It further defines a small group of patients and confirms that there is something odd about trisomy 12 cases that makes them stand out from the rest of CLLs. There is a small prognostic impact which is extra information, but I have to think that this is a work in progress. Which is why it has been published in B J Haem and not in Blood.

2 comments:

Wayne said...

Terry,
Would the translocations involving 14q be a meaningful marker for prognosis of general health regarding infections as opposed to cancer cell behavior and can these questions be meaningfully separated?

It would seem that a determination of what constitutes a damaged immune system is unclear. IgG,A & M levels do not appear to be the whole story regarding a healthy immune system.

Would a more complete set of markers alter the need and amount of prophylatic medications to benefit the individual patient when treatment for CLL is needed? Here I am thinking about some oncologist disagreement as to when Neupogen or Neulasta intervention is necessary based on different neutrophil (ANC) levels as a sole indicator.

CLL/SLL may not be a "good cancer" but I would not trade cancers with you! Hang in there mentor... Our thoughts are with you and ever present.

Practitioner of gratitude,
WWW

Terry Hamblin said...

Would the translocations involving 14q be a meaningful marker for prognosis of general health regarding infections as opposed to cancer cell behavior and can these questions be meaningfully separated?

No.

It would seem that a determination of what constitutes a damaged immune system is unclear. IgG,A & M levels do not appear to be the whole story regarding a healthy immune system.

True.

Would a more complete set of markers alter the need and amount of prophylatic medications to benefit the individual patient when treatment for CLL is needed? Here I am thinking about some oncologist disagreement as to when Neupogen or Neulasta intervention is necessary based on different neutrophil (ANC) levels as a sole indicator.

No evidence that any other markers help. The threshold for Neupogen is based on empiracal observations.