Genomic profiling of pleomorphic rhabdomyosarcoma reveals a genomic signature distinct from that of embryonal rhabdomyosarcoma Journal Article
| Authors: | Saoud, C.; Dermawan, J. K.; Sharma, A. E.; Tap, W.; Wexler, L. H.; Antonescu, C. R. |
| Article Title: | Genomic profiling of pleomorphic rhabdomyosarcoma reveals a genomic signature distinct from that of embryonal rhabdomyosarcoma |
| Abstract: | Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31–76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable. © 2024 Wiley Periodicals LLC. |
| Keywords: | adult; clinical article; controlled study; human tissue; protein expression; treatment response; aged; middle aged; cancer surgery; overall survival; somatic mutation; exon; gene deletion; genetics; missense mutation; mutation; clinical feature; histopathology; cancer recurrence; doxorubicin; cancer risk; bone metastasis; gemcitabine; temozolomide; nuclear magnetic resonance imaging; lymph node metastasis; genetic analysis; gene; disease association; progression free survival; classification; image analysis; tumor volume; ubiquitin protein ligase; etoposide; cohort analysis; genetic association; gene frequency; cyclophosphamide; vincristine; pathology; protein p53; tumor marker; oncogene h ras; histology; cancer mortality; distant metastasis; ifosfamide; high risk patient; carcinogenesis; docetaxel; irinotecan; sarcoma; lung metastasis; dna; heterozygosity; contrast enhancement; adjuvant chemotherapy; dactinomycin; genomics; physical examination; cyclin dependent kinase inhibitor 2a; mesna; rhabdomyosarcoma; cytokeratin; chromosome 8; adjuvant radiotherapy; loss of function mutation; ubiquitin-protein ligases; b raf kinase; fluorodeoxyglucose; embryonal; embryonal rhabdomyosarcoma; rhabdomyosarcoma, embryonal; chromosome 6q; myogenin; larynx surgery; pelvis surgery; braf gene; orthopedic surgery; chromosome 17p; chromosome 22q; smooth muscle actin; notch3 receptor; bone sarcoma; intermediate risk patient; copy number variation; fibromyxosarcoma; oncogene n ras; retinoblastoma binding protein; germline mutation; pleomorphic; procedures; cdkn2a gene; olaratumab; fibroblast growth factor receptor 4; abdominal metastasis; pharynx tumor; tp53 gene; low risk patient; rb1 gene; nf1 gene; high throughput sequencing; high-throughput nucleotide sequencing; gain of function mutation; mesentery tumor; atrx gene; dna sequencing; humans; human; male; female; article; myod1 protein; pembrolizumab; dicer1 gene; arid1b gene; pleomorphic rhabdomyosarcoma; biomarkers, tumor; positron emission tomography-computed tomography; vinorelbine tartrate; transcriptional regulator atrx; tumor mutational burden; notch3 gene; fgfr4 gene; desmin (protein); rb1 protein, human; retinoblastoma binding proteins; pelvic sarcoma; laryngeal sarcoma; muscle rhabdomyosarcoma; retropharyngeal sarcoma |
| Journal Title: | Genes Chromosomes and Cancer |
| Volume: | 63 |
| Issue: | 5 |
| ISSN: | 1045-2257 |
| Publisher: | Wiley Periodicals, Inc |
| Date Published: | 2024-05-01 |
| Start Page: | e23238 |
| Language: | English |
| DOI: | 10.1002/gcc.23238 |
| PUBMED: | 38722224 |
| PROVIDER: | scopus |
| PMCID: | PMC11664927 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Cristina R. Antonescu -- Source: Scopus |
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