Pan-Genomic Sequencing Reveals Actionable CDKN2A/2B Deletions and Kataegis in Anaplastic Thyroid Carcinoma

SIMPLE SUMMARY: Anaplastic thyroid carcinoma (ATC) is a tumor with exceedingly high mortality rates, and current treatment options are very limited once the disease has spread beyond the thyroid gland. Most of what we know of ATCs from a genetic standpoint is based upon previous analyses in which limited DNA segments are sequenced, and little is known about the so-called non-coding DNA regions. To identify novel genetic mechanisms of potential therapeutic use, we sequenced the entire genome of eight ATC cases and corresponding normal tissues. We found a recurrent deletion of two neighboring genes responsible for inhibiting cell division, and these findings may be of clinical interest as there are specific drugs available for tumors with this gene aberration. We also found regional aggregations of mutations in specific clusters, a phenomenon entitled “kataegis”, which in turn could be therapeutically relevant. ABSTRACT: 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 cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, 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 CDKN2A/2B 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.