Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies Journal Article
| Authors: | Dermawan, J. K.; Chi, P.; Tap, W. D.; Rosenbaum, E.; D'Angelo, S.; Alektiar, K. M.; Antonescu, C. R. |
| Article Title: | Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies |
| Abstract: | MYC amplifications have been frequently detected in radiation (RT)-associated angiosarcomas (ASs) by low-resolution molecular methods. However, large-scale next-generation sequencing (NGS) studies to investigate the genomic landscape of RT-AS are scarce, particularly compared with other RT-associated sarcomas. We performed a detailed comparative genomic investigation of RT-AS versus other RT-associated histotypes, as well as sporadic sarcomas with similar histologies. Our institutional targeted DNA-NGS assay database was searched for RT-associated sarcomas. Clinical outcome data, pathologic diagnosis, and the types and frequencies of genomic alterations, including single nucleotide variants (SNVs) and copy number alterations (CNAs), were analyzed. The cohort consisted of 82 patients, 68 (83%) females and 14 (17%) males, aged 37–88 (mean 64) years. Forty-four RT-ASs (38 from breast) and 38 RT sarcomas of other histologies, including 12 malignant peripheral nerve sheath tumors (RT-MPNSTs), 14 undifferentiated pleomorphic sarcomas (RT-UPSs), and 12 osteosarcomas (RT-OSs), were included. Median time intervals from radiation to initial diagnosis in RT-AS (8.0 years) were significantly lower than those in RT-MPNST and RT-UPS (12.5 and 18.5 years), respectively. Each RT-sarcoma histotype harbored distinct mutations and CNAs. RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX), whereas the mutational landscapes of MPNST, UPS, and OS were similar in both RT and non-RT settings. CDKN2A/B deletions and TP53 alterations were infrequent in RT-AS compared with other RT sarcomas. Among RT sarcomas, RT-AS harbored the lowest fraction of genome altered (FGA), while RT-MPNST showed the highest FGA. RT-AS had the lowest insertion:SNV and deletion:SNV ratios, while RT-UPS had the highest. The predominant mutational signatures were associated with errors in DNA repair and replication. In conclusion, RT-AS has a distinct genomic landscape compared with other RT sarcomas and sporadic AS. Potential molecular targets for precision medicine may be histotype-dependent. © 2023 The Pathological Society of Great Britain and Ireland. © 2023 The Pathological Society of Great Britain and Ireland. |
| Keywords: | osteosarcoma; adult; cancer survival; controlled study; human tissue; aged; bone neoplasms; survival analysis; bone tumor; gene mutation; major clinical study; single nucleotide polymorphism; gene deletion; genetics; histopathology; cancer diagnosis; dna replication; animal; animals; gene; dna repair; cohort analysis; pathology; angiosarcoma; mutational analysis; hemangiosarcoma; sarcoma; genomics; cancer classification; gene insertion; malignant peripheral nerve sheath tumor; mpnst; oncogene myc; gene structure; molecular profiling; genetic database; equidae; copy number variation; clinical outcome; hras gene; comparative genomics; cdkn2a gene; indel mutation; radiation-associated; tp53 gene; high throughput sequencing; dna sequencing; undifferentiated pleomorphic sarcoma; humans; human; male; female; article; neurofibrosarcoma; kmt2d gene; cdkn2b gene; radiation induced cancer; crkl gene; flt4 gene |
| Journal Title: | Journal of Pathology |
| Volume: | 260 |
| Issue: | 4 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2023-08-01 |
| Start Page: | 465 |
| End Page: | 477 |
| Language: | English |
| DOI: | 10.1002/path.6137 |
| PUBMED: | 37350195 |
| PROVIDER: | scopus |
| PMCID: | PMC10756077 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Cristina Antonescu -- Source: Scopus |
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