Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid Carcinoma
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 &l...
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/24/6340 |
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| author | Adam Stenman Minjun Yang Johan O. Paulsson Jan Zedenius Kajsa Paulsson C. Christofer Juhlin |
| author_facet | Adam Stenman Minjun Yang Johan O. Paulsson Jan Zedenius Kajsa Paulsson C. Christofer Juhlin |
| author_sort | Adam Stenman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:31:30Z |
| format | Article |
| id | doaj.art-1c1ad3fe66114c6d8482a634ecc5a0e6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:31:30Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1c1ad3fe66114c6d8482a634ecc5a0e62023-11-23T04:07:20ZengMDPI AGCancers2072-66942021-12-011324634010.3390/cancers13246340Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid CarcinomaAdam Stenman0Minjun Yang1Johan O. Paulsson2Jan Zedenius3Kajsa Paulsson4C. Christofer Juhlin5Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, SwedenDepartment of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22185 Lund, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, SwedenDepartment of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22185 Lund, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, SwedenAnaplastic 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.https://www.mdpi.com/2072-6694/13/24/6340anaplastic thyroid carcinomawhole-genome sequencingCDKN2ACDKN2Bkataegismolecular targets |
| spellingShingle | Adam Stenman Minjun Yang Johan O. Paulsson Jan Zedenius Kajsa Paulsson C. Christofer Juhlin Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid Carcinoma Cancers anaplastic thyroid carcinoma whole-genome sequencing CDKN2A CDKN2B kataegis molecular targets |
| title | Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid Carcinoma |
| title_full | Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid Carcinoma |
| title_fullStr | Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid Carcinoma |
| title_full_unstemmed | Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid Carcinoma |
| title_short | Pan-Genomic Sequencing Reveals Actionable <i>CDKN2A/2B</i> Deletions and Kataegis in Anaplastic Thyroid Carcinoma |
| title_sort | pan genomic sequencing reveals actionable i cdkn2a 2b i deletions and kataegis in anaplastic thyroid carcinoma |
| topic | anaplastic thyroid carcinoma whole-genome sequencing CDKN2A CDKN2B kataegis molecular targets |
| url | https://www.mdpi.com/2072-6694/13/24/6340 |
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