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Juhlin. Cancer Drug Resist 2020;3:992-1000 I http://dx.doi.org/10.20517/cdr.2020.66 Page 997

Relevance for future therapeutic interventions
Given the dismal overall prognosis and the limited treatment options for ATC patients, numerous in vitro
and clinical studies focusing on various adjuvant therapies have been launched in recent years, including
studies using immunotherapy (i.e., antibodies targeting PD-L1 and/or PD-1), epigenetic silencing (i.e.,
histone deacetylate inhibitors), metabolic pathway interference (i.e., stearoyl-CoA desaturase 1 inhibitors),
[5]
as well as specific gene therapies using an adenovirus vector . Immunotherapy seems especially promising
[30]
given the high frequency of PD-L1 and PD-1 positive ATC cells in clinical samples , as well as initial
studies suggesting partial response or stable disease in subsets of patients after immunotherapy [31,32] .
Interestingly, in unrelated tumor types, the expression of PD-L1 and the prognosis of patients receiving
immune checkpoint inhibitors have been found to be influenced by the MMR status and somatic mutations
in MMR genes [33-36] . If the same is true for ATC patients is not currently known, but given the known
association between aberrant MMR and the development of this highly lethal tumor type, studies on this
topic are highly warranted.

In colorectal cancer, there is an association between MMR-deficient tumors and an observed resistance to
[37]
various chemotherapeutic drugs used, not least 5-fluorouracil . For this reason, numerous studies have
been conducted in order to identify additional therapeutic options for cancers with an MMR deficiency.
In one study, the authors selectively knocked-down the function of DNA polymerases POLB and POLG
in cell lines deficient in MSH2 and MHL1 respectively, causing oxidative DNA lesions and lethal double
[38]
strand breaks . Moreover, cytarabine, a cytosine nucleoside analogue, has been proposed as an alternative
[39]
oxidative stress-generating compound with selectivity towards MMR deficient cell lines . Interestingly,
the folic acid antagonist methotrexate might work in a similar way, as studies have shown an increased
[40]
lethality for MSH2 mutated tumors via the induction of oxidative stress and extensive DNA damage .
To build on this, studies depicting partial responses in ATC patients administered oral methotrexate in
combinations with other cytotoxic drugs have been reported, but the MMR status of these tumors was
never characterized [41,42] . Finally, one should not overlook the potential of gene therapy, for example the
usage of out-of-frame “suicide genes”. When introduced in MMR deficient cells, the gene is randomly
[43]
reverted back to its in-frame version due to the hypermutability, leading to apoptosis .

DISCUSSION
Recent advances in NGS techniques have facilitated the genomic interrogation of thyroid tumors, allowing
for a detailed description of the mutational and chromosomal landscapes. This in turn has increased
our understanding of common driver events in thyroid tumorigenesis as well as highlighted markers of
diagnostic, prognostic, and therapeutic value in the clinical setting.

In the study outlined above, the authors amassed evidence for the progressive model, as thyroid tumors
were clonally linked, further supporting the theory that thyroid cancer dedifferentiation in this case was
a chained genetic event rather than synchronous manifestations of tumors arising separately by random
chance. Moreover, it seems tempting to speculate that a proportion of ATCs develop as a consequence of
aberrant DNA repair mechanisms due to somatic inactivation of MMR genes in pre-existing WDTCs, in
turn leading to hypermutability and the generation of multiple tumor sub-clones, of which some might give
rise to an undifferentiated phenotype [Figure 1]. In this aspect, the progression of ATC could be looked
at as a “genetic tombola”, in which hypermutability in preceding tumor forms (in our case exemplified
by a PDTC) will generate a massive amount of sub-clones, of which single ones will acquire additional
tumor-propagating mutations and/or gross chromosomal events, thus gaining a selective advantage and
emerging as highly lethal ATCs. However, it should be stated that the majority of ATCs do not exhibit
hypermutability and defective MMR, and therefore additional genetic and/or epigenetic events are most
probably responsible for the dedifferentiation in these cases.