Classical JAK2V617F+ Myeloproliferative Neoplasms emergence and development based on real life incidence and mathematical modeling

TL;DR

This study uses mathematical modeling to analyze the emergence and development of JAK2V617F+ myeloproliferative neoplasms, revealing age-dependent mutation rates and estimating the timeframes for disease progression.

Contribution

It introduces an age-dependent mathematical model for MPN development, highlighting the exponential increase in mutation rate and providing estimates for mutation and expansion times.

Findings

Mutation occurrence rate increases exponentially with age.

Average mutation appearance time is approximately 63 years.

Expansion time from mutation to diagnosis is about 8.8 years.

Abstract

Mathematical modeling allows us to better understand myeloproliferative neoplasms (MPN), a group of blood cancers, emergence and development. We test different mathematical models on an initial cohort to determine the emergence and evolution times before diagnosis of JAK2V617F+ classical MPN (Polycythemia Vera (PV) and Essential Thrombocythemia (ET)). We consider the time before diagnosis as the sum of two independent periods: the time (from embryonic development) for the JAK2V617F mutation to occur, not disappear and enter proliferation, and a second time corresponding to the expansion of the clonal population until diagnosis. We prove that the rate of active mutation occurrence increases exponentially with age following the Gompertz model rather than being constant. We find that the first tumorous cell takes an average time of $63.1 \pm 13$ years to appear and start proliferation. On the other hand, the expansion time is constant: $8.8$ years once the mutation has emerged. These results are validated in an external cohort. Using this model, we analyze JAK2V617F ET versus PV, and obtain that the time of active mutation occurrence for PV takes approximately $1.5$ years more than for ET to develop, while the expansion time was similar. In conclusion, our age-dependent approach for the emergence and development of MPN demonstrates that the emergence of a JAKV617F mutation should be linked to an aging mechanism, and indicates a $8-9$ years period of time to develop a full MPN.