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Pan-genomic sequencing reveals actionable cdkn2a/2b deletions and kataegis in anaplastic thyroid carcinoma

Stenman, Adam ; Yang, Minjun LU ; Paulsson, Johan O. ; Zedenius, Jan ; Paulsson, Kajsa LU and Juhlin, C. Christofer (2021) In Cancers 13(24).
Abstract

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations... (More)

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of CDKN2A/2B in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anaplastic thyroid carcinoma, CDKN2A, CDKN2B, Kataegis, Molecular targets, Whole-genome sequencing
in
Cancers
volume
13
issue
24
article number
6340
publisher
MDPI AG
external identifiers
  • pmid:34944959
  • scopus:85121313931
ISSN
2072-6694
DOI
10.3390/cancers13246340
language
English
LU publication?
yes
id
3fa003ad-9b96-4c42-b6c4-97766433756f
date added to LUP
2022-01-27 11:22:59
date last changed
2024-06-16 00:35:25
@article{3fa003ad-9b96-4c42-b6c4-97766433756f,
  abstract     = {{<p>Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of CDKN2A/2B in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors.</p>}},
  author       = {{Stenman, Adam and Yang, Minjun and Paulsson, Johan O. and Zedenius, Jan and Paulsson, Kajsa and Juhlin, C. Christofer}},
  issn         = {{2072-6694}},
  keywords     = {{Anaplastic thyroid carcinoma; CDKN2A; CDKN2B; Kataegis; Molecular targets; Whole-genome sequencing}},
  language     = {{eng}},
  number       = {{24}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Pan-genomic sequencing reveals actionable cdkn2a/2b deletions and kataegis in anaplastic thyroid carcinoma}},
  url          = {{http://dx.doi.org/10.3390/cancers13246340}},
  doi          = {{10.3390/cancers13246340}},
  volume       = {{13}},
  year         = {{2021}},
}