Identification of Targetable Lesions in Anaplastic Thyroid Cancer by Genome Profiling

Abstract

Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations. A high frequency of genomic amplifications was seen, including 29% of cases having amplification of CCNE1 and 9% of CDK6; these events may be targetable by cyclin dependent kinase (CDK) inhibition. Furthermore, 9% harbored amplification of TWIST1, which is also a potentially targetable lesion. A total of 21 fusion genes in five cases were seen, none of which were recurrent. Frequent mutations included TP53 (55%), the TERT promoter (36%), and ATM (27%). Analyses of mutational signatures showed an involvement of processes that are associated with normal aging, defective DNA mismatch repair, activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity, failure of DNA double-strand break repair, and tobacco exposure. Taken together, our results shed new light on the tumorigenesis of ATC and show that a relatively large proportion (36%) of ATCs harbor genetic events that make them candidates for novel therapeutic approaches. When considering that ATC today has a mortality rate of close to 100%, this is highly relevant from a clinical perspective.

Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer

“…In regards to DNA methylation, the majority of differentially methylated CpGs in ATC were hypomethylated and in intergenic regions (Figure 2), in line with previous studies [10,11,24]. Global hypomethylation is a common phenomenon in cancer and is believed to be associated with genomic instability [25], agreeing well with the genomic complexity generally seen in ATC [20]. Conversely, most hypermethylated CpG sites were in CpG islands, indicating specific effects on gene expression.…”

“…In cancer, TWIST1 has been shown to be involved in epithelial-mesenchymal transition and to promote metastasis [35]. Notably, we have previously reported that TWIST1 is sometimes amplified in primary ATC (#2 in the present study) [20]. Thus, aberrant activation of TWIST1-associated pathways, either by copy number changes or by aberrant methylation, could be a recurrent event in ATC.…”

“…This case was also one of two which showed a relatively high thyroid differentiation score (Figure 1b), showing that the correlation between the NRAS-BRAF and thyroid differentiation scores seen in the TCGA study was preserved in our dataset. Notably, we have previously reported that case 12 was also an outlier in terms of mutational pattern, with a very high number of somatic mutations, a different mutational signature, possible microsatellite instability, and occurring in a relatively young patient [20].…”

“…DAVID pathway analysis showed enrichment for genes involved in cell adhesion and transcription (Table S9). [20]. N/A, not applicable.…”

“…The study included a total of 14 primary cases of ATC previously included in Ravi et al [20] ( Table 1); somatic mutations and gene fusions have been previously reported. Cases were selected based on not having obtained chemotherapy or radiotherapy treatment prior to sampling, sample availability, and >30% tumor cells based on the pathologist's estimate and/or copy number aberrations or mutations detected by whole-exome sequencing (WES).…”