JAK2 617V>F positive polycythemia rubra vera maintained by approximately 18 stochastic stem-cell divisions per year, explaining age of onset by a single rate-limiting mutation.
As the rates of most cancers are proportional to the fourth to fifth power of age ("log-log" behavior), it is widely believed that 5 to 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 ( approximately 18 per year) differentiation events. These parameters imply that malignant stem cells have a modest selective advantage. Correspondingly minor, typically less than 20%, increases in stochastic self-renewal ratios are modeled to show that single mutations can result in the observed fourth power relationship with age. The conundrum between log-log behavior 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."
Vickers
Mark A
MA
Department of Medicine and Therapeutics, Aberdeen University Medical School, Aberdeen, United Kingdom. m.a.vickers@abdn.ac.uk
D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics*; D006021:Glycophorins / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011087:Polycythemia Vera / Q000235:genetics* / Q000503:physiopathology; D040641:Quantitative Trait Loci / Q000235:genetics*; D013997:Time Factors
D006021:Glycophorins; C507924:JAK2 protein, human; D053614:Janus Kinase 2