Fig. 1.

Model of cancer evolution

an initial transforming event (Initial Event) converts a normal stem/progenitor cell into a somatically mutated clonal stem cell. In case the stem cell can survive and retains self-renewal capacity, it has become a neoplastic premalignant stem cell (Early Lesions). Usually, these cells are slowly cycling cells or dormant cells and contain passenger mutations. After several years or decades, the resulting clone has acquired first driver lesions and expands and may have replaced some or most of the polyclonal cells in the normal organ (First Driver Lesions). At that time, neoplastic cells and normal cells are often indistinguishable by morphology or in functional terms. In a next step, one or more sub-clones acquire additional driver-lesions (Additional Lesions). Depending on the type of lesion and the type of preformed clones and their passenger signature, the resulting new subclones may either expand immediately, or may again reside in a slowly cycling or even dormant stage. In these patients, the driver mutation may or may not be detectable depending on the size of the affected sub-clones. However, as soon as additional driver lesions have been acquired, the resulting sub-clones can finally expand and replace the normal organ (Complex Multi-Lesion Patterns). In many cases, the created neoplasm may still behave as an indolent driver-positive neoplasms for some time. However, unless treated, many of these conditions will finally progress to an aggressive malignancy.