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Genomic complexity and targeted genes in anaplastic thyroid cancer cell lines

Woodward, Eleanor L LU ; Biloglav, Andrea LU ; Ravi, Naveen LU ; Yang, Minjun LU ; Ekblad, Lars LU orcid ; Wennerberg, Johan LU orcid and Paulsson, Kajsa LU (2017) In Endocrine-Related Cancer 24(5). p.209-220
Abstract

Anaplastic thyroid cancer (ATC) is a highly malignant disease with a very short median survival time. Few studies have addressed the underlying somatic mutations, and the genomic landscape of ATC thus remains largely unknown. In the present study, we have ascertained copy number aberrations, gene fusions, gene expression patterns, and mutations in early-passage cells from ten newly established ATC cell lines using single nucleotide polymorphism (SNP) array analysis, RNA sequencing and whole exome sequencing. The ATC cell line genomes were highly complex and displayed signs of replicative stress and genomic instability, including massive aneuploidy and frequent breakpoints in the centromeric regions and in fragile sites. Loss of... (More)

Anaplastic thyroid cancer (ATC) is a highly malignant disease with a very short median survival time. Few studies have addressed the underlying somatic mutations, and the genomic landscape of ATC thus remains largely unknown. In the present study, we have ascertained copy number aberrations, gene fusions, gene expression patterns, and mutations in early-passage cells from ten newly established ATC cell lines using single nucleotide polymorphism (SNP) array analysis, RNA sequencing and whole exome sequencing. The ATC cell line genomes were highly complex and displayed signs of replicative stress and genomic instability, including massive aneuploidy and frequent breakpoints in the centromeric regions and in fragile sites. Loss of heterozygosity involving whole chromosomes was common, but there were no signs of previous near-haploidisation events or chromothripsis. A total of 21 fusion genes were detected, including six predicted in-frame fusions; none were recurrent. Global gene expression analysis showed 661 genes to be differentially expressed between ATC and papillary thyroid cancer cell lines, with pathway enrichment analyses showing downregulation of TP53 signalling as well as cell adhesion molecules in ATC. Besides previously known driver events, such as mutations in BRAF, NRAS, TP53 and the TERT promoter, we identified PTPRD and NEGR1 as putative novel target genes in ATC, based on deletions in six and four cell lines, respectively; the latter gene also carried a somatic mutation in one cell line. Taken together, our data provide novel insights into the tumourigenesis of ATC and may be used to identify new therapeutic targets.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Endocrine-Related Cancer
volume
24
issue
5
pages
12 pages
publisher
Society for Endocrinology
external identifiers
  • pmid:28235956
  • scopus:85019060357
  • wos:000402140200005
ISSN
1479-6821
DOI
10.1530/ERC-16-0522
language
English
LU publication?
yes
id
ca48ce1c-6398-468b-b722-9e9d283eb856
date added to LUP
2017-05-03 12:42:26
date last changed
2025-01-07 12:24:24
@article{ca48ce1c-6398-468b-b722-9e9d283eb856,
  abstract     = {{<p>Anaplastic thyroid cancer (ATC) is a highly malignant disease with a very short median survival time. Few studies have addressed the underlying somatic mutations, and the genomic landscape of ATC thus remains largely unknown. In the present study, we have ascertained copy number aberrations, gene fusions, gene expression patterns, and mutations in early-passage cells from ten newly established ATC cell lines using single nucleotide polymorphism (SNP) array analysis, RNA sequencing and whole exome sequencing. The ATC cell line genomes were highly complex and displayed signs of replicative stress and genomic instability, including massive aneuploidy and frequent breakpoints in the centromeric regions and in fragile sites. Loss of heterozygosity involving whole chromosomes was common, but there were no signs of previous near-haploidisation events or chromothripsis. A total of 21 fusion genes were detected, including six predicted in-frame fusions; none were recurrent. Global gene expression analysis showed 661 genes to be differentially expressed between ATC and papillary thyroid cancer cell lines, with pathway enrichment analyses showing downregulation of TP53 signalling as well as cell adhesion molecules in ATC. Besides previously known driver events, such as mutations in BRAF, NRAS, TP53 and the TERT promoter, we identified PTPRD and NEGR1 as putative novel target genes in ATC, based on deletions in six and four cell lines, respectively; the latter gene also carried a somatic mutation in one cell line. Taken together, our data provide novel insights into the tumourigenesis of ATC and may be used to identify new therapeutic targets.</p>}},
  author       = {{Woodward, Eleanor L and Biloglav, Andrea and Ravi, Naveen and Yang, Minjun and Ekblad, Lars and Wennerberg, Johan and Paulsson, Kajsa}},
  issn         = {{1479-6821}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{209--220}},
  publisher    = {{Society for Endocrinology}},
  series       = {{Endocrine-Related Cancer}},
  title        = {{Genomic complexity and targeted genes in anaplastic thyroid cancer cell lines}},
  url          = {{http://dx.doi.org/10.1530/ERC-16-0522}},
  doi          = {{10.1530/ERC-16-0522}},
  volume       = {{24}},
  year         = {{2017}},
}