title: 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 ofTP53signalling as well as cell adhesion molecules in ATC. Besides previously known driver events, such as mutations inBRAF,NRAS,TP53and theTERTpromoter, we identifiedPTPRDandNEGR1as 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.
authors.affiliation: Division of Clinical GeneticsDepartment of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Eleanor L
authors.initials: EL
authors.lastname: Woodward
authors.affiliation: Division of Clinical GeneticsDepartment of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biloglav
authors.affiliation: Division of Clinical GeneticsDepartment of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Naveen
authors.initials: N
authors.lastname: Ravi
authors.affiliation: Division of Clinical GeneticsDepartment of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Minjun
authors.initials: M
authors.lastname: Yang
authors.affiliation: Division of Oncology and PathologyClinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Ekblad
authors.affiliation: Division of Otorhinolaryngology/Head and Neck SurgeryClinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Wennerberg
authors.affiliation: Division of Clinical GeneticsDepartment of Laboratory Medicine, Lund University, Lund, Sweden kajsa.paulsson@med.lu.se.
authors.forename: Kajsa
authors.initials: K
authors.lastname: Paulsson
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study; D042822:Genomic Instability; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017423:Sequence Analysis, RNA; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics*
keywords: gene expression; molecular genetics; thyroid