Abstract
Well-differentiated thyroid carcinoma (WDTC, including papillary thyroid carcinoma and follicular thyroid carcinoma) are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy. Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), of which especially the latter has an exceptionally poor patient outcome. The underlying genetics responsible for this tumor progression is only partly understood, and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable, pre-existing WDTC. Even so, recent advances using next generation sequencing (NGS) techniques have identified a genetic link between WDTCs and ATCs, suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases. In this Commentary, recent findings from an NGS study on synchronous FTC, PDTC, and ATC tumor components from the same patient are highlighted. By using whole-genome data, clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair, with sub-clones in each tumor component that were identified also in the less differentiated, neighboring tumor. Moreover, mutational signatures suggested a general mismatch repair (MMR) deficiency along with microsatellite instability. These findings support the chained progression model of dedifferentiation in thyroid cancer, and pinpoint a central role for defective DNA repair. Since effective treatment modalities for ATCs are urgently needed, studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.
Highlights
Anaplastic thyroid carcinoma: a clinical background rare, anaplastic thyroid carcinoma (ATC) is a highly lethal form of thyroid cancer[1,2]
[12] this study vaguely suggests that the tumors might have evolved from different mother clones, a tumoral evolution from WDTC to ATC via progressive genomic instability could not be excluded either
By recent next generation sequencing (NGS) studies, the mutational landscapes of poorly differentiated thyroid carcinoma (PDTC) and ATCs have been partly deciphered, and the results indicate that a large proportion of cases exhibit common driver mutations normally seen in WDTCs[13,14]
Summary
Anaplastic thyroid carcinoma (ATC) is a highly lethal form of thyroid cancer[1,2]. Data from paired WES studies of WDTCs and ATCs are accumulating, and the majority of cases seem to exhibit a common and short phylogenetic tree trunk with identical mutational profiles adjoined by disparate mutations as a consequence of the tumors separating early in clonal evolution[17,18]. These data strongly imply that ATCs, whenever a synchronous WDTC is visualized, do arise by dedifferentiation from a pre-existing WDTC, highly important information from preventive and therapeutic angles. The reason for the increase in gross structural abnormalities observed in ATCs compared to WDTCs is not fully established
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