Abstract
Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations. A high frequency of genomic amplifications was seen, including 29% of cases having amplification of CCNE1 and 9% of CDK6; these events may be targetable by cyclin dependent kinase (CDK) inhibition. Furthermore, 9% harbored amplification of TWIST1, which is also a potentially targetable lesion. A total of 21 fusion genes in five cases were seen, none of which were recurrent. Frequent mutations included TP53 (55%), the TERT promoter (36%), and ATM (27%). Analyses of mutational signatures showed an involvement of processes that are associated with normal aging, defective DNA mismatch repair, activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity, failure of DNA double-strand break repair, and tobacco exposure. Taken together, our results shed new light on the tumorigenesis of ATC and show that a relatively large proportion (36%) of ATCs harbor genetic events that make them candidates for novel therapeutic approaches. When considering that ATC today has a mortality rate of close to 100%, this is highly relevant from a clinical perspective.
Highlights
Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor, with close to 100% mortality and no available cure [1,2,3,4]
Cytogenetic analysis and array comparative genome hybridization of ATC has revealed high levels of aneuploidy, with chromosome numbers ranging from 65–120; these studies were performed on small cohorts of samples [5,6,7,8,9,10,11]
Copy number analysis could be undertaken based on whole exome seuencing (WES) data in 10 cases (Table 1)
Summary
Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor, with close to 100% mortality and no available cure [1,2,3,4]. The lack of curative treatments for ATC makes it important to understand the underlying tumorigenesis of this disease; the genomic landscape of ATC has not yet been fully delineated. Cytogenetic analysis and array comparative genome hybridization (aCGH) of ATC has revealed high levels of aneuploidy, with chromosome numbers ranging from 65–120; these studies were performed on small cohorts of samples [5,6,7,8,9,10,11]. Cancers 2019, 11, 402 to structural rearrangements, a STRN-ALK translocation has been found in one case of ATC [12], but no recurrent gene fusions have been identified. Genes that are recurrently mutated in ATC include TP53 (25–60% of cases), BRAF (25–90%), USH2A (20%), NRAS (15–20%), PTEN (15%), NF1
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