Genomic complexity and targeted genes in anaplastic thyroid cancer cell lines

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 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 signalling as well as cell adhesion molecules in ATC. Besides previously known driver events, such as mutations in, , and the promoter, we identified and 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.

Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

“…Other cautions about PTPRD as a target for novel therapeutic agents come from associations between (i) total, lifelong human or mouse PTPRD KO and cognitive difficulties (5,32) and (ii) findings that rare variation likely to dramatically alter PTPRD expression can promote or inhibit cancer formation or properties of cancer cells (33,34). Neither humans nor mice with moderate differences in levels of PTPRD expression display any cognitive abnormalities.…”

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

“…There are reported associations between PTPRD variation and a number of cancers or their responses to treatment . While the details of these associations are beyond the scope of this paper, we note that most come from genotyping tumors or tumor‐derived cell lines and that none of these associations focuses on the mid‐gene regions that we have associated with a number of brain phenotypes and levels of PTPRD expression.…”

Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines

“…Seven of the cell lines had mutations in the TP53 gene, of which five were homozygous, including a homozygous deletion of exon 2-9 in LU-TC-14 ( Table 5). In addition to the previously reported TP53 mutations reported in Woodward et al [5], the reanalysis resulted in detection of additional mutations in LU-TC-2 and LU-TC-12 ( Table 5).…”

“…Samples were electrophoresed on a 3130xl Genetic Analyzer (Applied Biosystems) and MLPA analysis was performed using the genotype analysis software Genemarker (SoftGenetics, State College, PA, USA). Furthermore, whole exome sequencing data from Woodward et al [5] were reanalysed regarding TP53 mutational status using ANNOVAR.…”

“…The cell lines have previously been extensively characterized on the genetic level [5]. In this work we further analysed the mutational status of RET, BRAF and TP53.…”