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

• Published in: Cancers Vol. 13; no. 24; p. 6340
• Main Authors: Stenman, Adam, Yang, Minjun, Paulsson, Johan O, Zedenius, Jan, Paulsson, Kajsa, Juhlin, C Christofer
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.12.2021; MDPI
• Subjects: Airway management; Anaplastic thyroid carcinoma; Apolipoprotein B; Basic Medicine; Biobanks; CDKN2A; CDKN2B; CDKN2B gene; Cell division; Chemotherapy; Copy number; Cyclin-dependent kinase; Data analysis; Deoxyribonucleic acid; DNA; Enzyme inhibitors; Gene expression; Genetic analysis; Genomes; Genomics; Immune checkpoint inhibitors; Immunosuppressive agents; Kataegis; Malignancy; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Metastasis; Molecular targets; mRNA; Mutation; Nucleotide sequence; p53 Protein; Patients; Phenotypes; RNA editing; Surgery; Thyroid cancer; Thyroid carcinoma; Tumors; Whole genome sequencing; Sweden; anaplastic thyroid carcinoma; CDKN2B; molecular targets; CDKN2A; kataegis; whole-genome sequencing
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13246340

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 ( ) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the locus (encoding p16 and p14arf) also exhibited loss of the neighboring gene (encoding p15ink4b), and displayed reduced mRNA levels. Mutations in established ATC-related genes were observed, including , , , and , 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 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.