Genomic complexity and targeted genes in anaplastic thyroid cancer cell lines
| Autor: | Kajsa Paulsson, Johan Wennerberg, Minjun Yang, Eleanor L. Woodward, Andrea Biloglav, Lars Ekblad, Naveen Ravi |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Somatic cell Endocrinology Diabetes and Metabolism Biology Thyroid Carcinoma Anaplastic Polymorphism Single Nucleotide Genomic Instability Loss of heterozygosity Fusion gene Genetic Heterogeneity 03 medical and health sciences Germline mutation Endocrinology Cell Line Tumor medicine Humans Molecular Targeted Therapy Anaplastic thyroid cancer Gene Exome sequencing Genetics Chromothripsis Sequence Analysis RNA Gene Expression Profiling High-Throughput Nucleotide Sequencing medicine.disease Gene Expression Regulation Neoplastic Cell Transformation Neoplastic 030104 developmental biology Oncology Mutation Genome-Wide Association Study |
| Zdroj: | Endocrine-Related Cancer. :X2 |
| ISSN: | 1479-6821 1351-0088 |
| DOI: | 10.1530/erc-16-0522e |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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