Friday, October 19, 2012

clonal evolution part 2

ASH plenary session link

I've written once previously about clonal evolution, but I think this is really an important topic and so I wanted to come back to it again.

There is a wonderful new technology called "next generation sequencing" that is turning cancer biology upside down.  The human genome project took 13 years, 6 billion dollars, and sequenced (ie measured every single piece of human DNA) the genome of four healthy individuals.  That is a lot of time and money.  You can now do the same (actually much more) amount of work in about 2-3 weeks at a cost getting closer and closer to $1000. 

When you can measure DNA at this level of depth at this cost you can start asking very important questions.  Take the following image:

This looks at an individual with CLL who had their cancer cells sequenced at 5 different timepoints in their disease.  I suspect this is true in lymphoma as well, but tissue is harder to get.  For now, assume this applies to both diseases.

At the first timepoint analyzed (a) there are already three "subclones" and a population of normal B cells.  The patient gets treated with chlorambucil and at timepoint (b) which is relapse following treatment, one clone has taken off as the major one (91%).  The patient then gets treated with FCR and overall the disease largely goes away.  Subclone 1 goes away forever.  Unfortunately subclone 4 which was only 1% of all the cells prior to FCR really takes off and becomes the clone that eventually causes the patient to get into trouble.

This highlights how the behavior of disease can change over time.  Different subclones may acquire different mutations (17p, 11q, BIRC3, SF3B1, NOTCH, etc.).  Though it may be lurking in background, it can become the predominant clone when exposed to therapies that eliminate the "easy disease."

I am not sure just yet if that makes an argument for how we treat patients, but I do think we aught to be looking to see how certain therapies affect patterns of resistance....