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Juhlin. Cancer Drug Resist 2020;3:992-1000 Cancer
DOI: 10.20517/cdr.2020.66 Drug Resistance

Commentary Open Access

Aberrant DNA repair as a potential contributor for
the clonal evolution in subsets of anaplastic thyroid

carcinomas arising through dedifferentiation:
implications for future therapeutic algorithms?

Carl Christofer Juhlin 1,2
1 Department of Oncology-Pathology, Karolinska Institutet, Stockholm SE-17176, Sweden.
2 Department of Pathology and Cytology, Karolinska University Hospital, Stockholm SE-17176, Sweden.
Correspondence to: Associate Prof. Carl Christofer Juhlin, Department of Pathology and Cytology, Karolinska University
Hospital, Radiumhemmet, P1:02, Stockholm SE-17176, Sweden. E-mail: christofer.juhlin@ki.se
How to cite this article: Juhlin CC. Aberrant DNA repair as a potential contributor for the clonal evolution in subsets of anaplastic
thyroid carcinomas arising through dedifferentiation: implications for future therapeutic algorithms? Cancer Drug Resist
2020;3:992-1000. http://dx.doi.org/10.20517/cdr.2020.66

Received: 18 Aug 2020 First Decision: 30 Sep 2020 Revised: 30 Sep 2020 Accepted: 14 Oct 2020 Available online: 3 Nov 2020
Academic Editor: Robert C.A.M. van Waardenburg Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

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

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
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