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Free keywords:
cancer; stem cells; mathematical models
Abstract:
The theory of the clonal origin of cancer states that a tumour arises from one
cell that acquires mutation(s) leading to the malignant phenotype. It is the
current belief that many of these mutations give a fitness advantage to
the mutant population allowing it to expand, eventually leading to disease.
However,mutations that lead to such a clonal expansion need not give a fitness
advantage and may in fact be neutral—or almost neutral—with respect to fitness.
Such mutant clones can be eliminated or expand stochastically, leading to
a malignant phenotype (disease). Mutations in haematopoietic stem cells give
rise to diseases such as chronic myeloid leukaemia (CML) and paroxysmal
nocturnal haemoglobinuria (PNH). Although neutral drift often leads to
clonal extinction, disease is still possible, and in this case, it has important
implications both for the incidence of disease and for therapy, as it may be
more difficult to eliminate neutral mutations with therapy. We illustrate the
consequences of such dynamics, using CML and PNH as examples. These
considerations have implications for many other tumours as well.
