fig1

Figure 1. Schematic representation of the genetic mechanisms observed in the evolution of DNA repair defective anaplastic thyroid carcinomas (ATCs) as outlined by Paulsson et al.^[26]. The two main hypotheses regarding formation of ATCs are shown, with most focus on the “dedifferentiation hypothesis”. In thyroid tumorigenesis, the normal thyrocyte is normally afflicted by a set of somatic gene mutations by random chance, possibly also influenced by exogenic factors and underlying rare constitutional variants in susceptibility genes, of which some are associated to DNA repair mechanisms (in this case MUTYH) (step 1a-2a). At this point, somatic mutations in DNA repair genes (e.g., MSH2) and microsatellite instability (MSI) is evident (step 2a). This leads to the formation of a well-differentiated thyroid carcinoma (WDTC), in this case an follicular thyroid carcinoma. Additional somatic mutations in driver genes and DNA repair genes along with increased MSI in a sub-clone (step 3) most likely influence the formation of a PDTC, which exhibits hypermutability and massive formation of additional tumor sub-clones (step 4), of which subsets of these could transform into an ATC following additional somatic mutations (step 5). The de novo hypothesis is outlined in step 1b-2b. Apart from driver gene mutations, little is known regarding the genetics propelling the formation of an ATC directly from a normal thyrocyte, without preceding tumor formations