Cancer-associated mutations in healthy individuals: assessing the risk of carcinogenesis
Cette étude présente un modèle mathématique susceptible d'estimer, chez des individus en bonne santé, le risque à long terme lié à la présence de mutations associées à des hémopathies malignes
Mutations associated with hematopoietic malignancies have been repeatedly identified in healthy individuals. For certain cases, such as the t(14;18) translocation and monoclonal B cell lymphocytosis, no clear link between the presence of aberrant cells and the later development of cancer has been established. Intriguingly, longitudinal studies suggest that these abnormalities persist for long periods of time in some individuals, but in others are transient where they disappear completely. Here we present a mathematical model, based on cellular replication limits, that provides a possible explanation for these seemingly contradictory findings. It proposes that the transient and persistent nature of the phenotypes depends on the stage in the differentiation pathway of a given lineage where the mutation originates. Our work suggests that cellular replication limits may not only prevent cancer by aborting clonal expansion of cells, but also by influencing the fate of altered but non-neoplastic cells in healthy tissue.
Major Findings : If the mutation originates in stem cells, long-term persistence of the mutants is likely, and this poses a significant risk for progression to cancer. If the mutation arises downstream, such as in progenitor cells, the presence of the mutants is likely to be transient and the risk of disease development is significantly lower. We propose experiments based on telomere length measurements that may make it possible to estimate the risk posed in individual patients by cancer-associated mutations found in healthy individuals.
Cancer Research , résumé, 2014