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Open AccessArticle

Identification of Targetable Lesions in Anaplastic Thyroid Cancer by Genome Profiling

1
Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, SE-221 84 Lund, Sweden
2
Division of Otorhinolaryngology/Head and Neck Surgery, Clinical Sciences, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
3
Division of Oncology and Pathology, Clinical Sciences, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(3), 402; https://doi.org/10.3390/cancers11030402
Received: 13 February 2019 / Revised: 13 March 2019 / Accepted: 19 March 2019 / Published: 22 March 2019
(This article belongs to the Special Issue Thyroid Cancer)
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. View Full-Text
Keywords: anaplastic thyroid cancer; whole exome sequencing; RNA-sequencing; formalin-fixed paraffin embedded tissues; fusion genes; somatic mutations; copy number alterations; CCNE1 anaplastic thyroid cancer; whole exome sequencing; RNA-sequencing; formalin-fixed paraffin embedded tissues; fusion genes; somatic mutations; copy number alterations; CCNE1
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Ravi, N.; Yang, M.; Gretarsson, S.; Jansson, C.; Mylona, N.; Sydow, S.R.; Woodward, E.L.; Ekblad, L.; Wennerberg, J.; Paulsson, K. Identification of Targetable Lesions in Anaplastic Thyroid Cancer by Genome Profiling. Cancers 2019, 11, 402.

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