| Summary: | Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed <i>cyclin-dependent kinase inhibitor 2A</i> (<i>CDKN2A</i>) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the <i>CDKN2A</i> locus (encoding p16 and p14arf) also exhibited loss of the neighboring <i>CDKN2B</i> gene (encoding p15ink4b), and displayed reduced <i>CDKN2A/2B</i> mRNA levels. Mutations in established ATC-related genes were observed, including <i>TP53</i>, <i>BRAF</i>, <i>ARID1A</i>, and <i>RB1</i>, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of <i>CDKN2A/2B</i> in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors.
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