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Identification of targetable lesions in anaplastic thyroid cancer by genome profiling

Ravi, Naveen LU ; Yang, Minjun LU ; Gretarsson, Sigurdur LU ; Jansson, Caroline LU ; Mylona, Nektaria ; Sydow, Saskia R. LU ; Woodward, Eleanor L. LU ; Ekblad, Lars LU orcid ; Wennerberg, Johan LU orcid and Paulsson, Kajsa LU (2019) In Cancers 11(3).
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anaplastic thyroid cancer, CCNE1, Copy number alterations, Formalin-fixed paraffin embedded tissues, Fusion genes, RNA-sequencing, Somatic mutations, Whole exome sequencing
in
Cancers
volume
11
issue
3
article number
402
publisher
MDPI AG
external identifiers
  • scopus:85064433116
  • pmid:30909364
ISSN
2072-6694
DOI
10.3390/cancers11030402
language
English
LU publication?
yes
id
730e8ab8-0ee2-49c5-8ac0-e6f1bed2ffd1
date added to LUP
2019-05-06 10:09:58
date last changed
2024-04-02 02:46:27
@article{730e8ab8-0ee2-49c5-8ac0-e6f1bed2ffd1,
  abstract     = {{<p>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.</p>}},
  author       = {{Ravi, Naveen and Yang, Minjun and Gretarsson, Sigurdur and Jansson, Caroline and Mylona, Nektaria and Sydow, Saskia R. and Woodward, Eleanor L. and Ekblad, Lars and Wennerberg, Johan and Paulsson, Kajsa}},
  issn         = {{2072-6694}},
  keywords     = {{Anaplastic thyroid cancer; CCNE1; Copy number alterations; Formalin-fixed paraffin embedded tissues; Fusion genes; RNA-sequencing; Somatic mutations; Whole exome sequencing}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Identification of targetable lesions in anaplastic thyroid cancer by genome profiling}},
  url          = {{http://dx.doi.org/10.3390/cancers11030402}},
  doi          = {{10.3390/cancers11030402}},
  volume       = {{11}},
  year         = {{2019}},
}