Submitted December 7, 2006
Accepted April 18, 2007
JAK2 V617F positive polycythemia rubra vera maintained by ~18 stochastic stem cell divisions/year, explaining age of onset by a single rate limiting mutation
Mark A Vickers*
Department of Medicine & Therapeutics, Aberdeen University Medical School, Aberdeen, United Kingdom
* Corresponding author; email: m.a.vickers{at}abdn.ac.uk.
As the rates of most cancers are proportional to the 4-5th power of age ('log-log' behaviour), it is widely believed that 5-6 independent mutations are necessary for malignant transformation. Conversely, the peak incidences of most cancers are similar to stem cell mutation rates at single loci, implying only one rate limiting mutation. Here, flow cytometrically measured red blood cells mutated at a selectively neutral locus, glycophorin A, allow observation of individual stem cell differentiation events in a log-log malignancy, polycythemia rubra vera. Contrary to predictions from multistep models, the clone is driven by infrequent (<annual) and rare (~18 per year) differentiation events. These parameters imply that malignant stem cells have a modest selective advantage. Correspondingly minor, typically <20%, increases in stochastic self-renewal ratios are modelled to show that single mutations can result in the observed 4th power relationship with age. The conundrum between log-log behaviour and mutation rate is thereby reconcilable, with the age of onset arising not from the requirement for multiple, independent mutations but from infrequent, stochastic stem cell division rates and single mutations causing initially minor effects, but initiating a clone whose expected number increases successively with age - an 'exponential phenotype'.
