Synapse - Undifferentiated pleomorphic sarcoma in children and young adults: A comprehensive clinicopathologic, genomic, and epigenetic comparison with adult counterparts

Undifferentiated pleomorphic sarcoma in children and young adults: A comprehensive clinicopathologic, genomic, and epigenetic comparison with adult counterparts Journal Article

Authors:	Saoud, C.; Gundem, G.; Vanderbilt, C. M.; Wexler, L. H.; Reed, D. R.; Tap, W.; Singer, S.; Villafania, L. B.; Papaemmanouil, E.; Benhamida, J.; Bale, T. A.; Antonescu, C. R.
Article Title:	Undifferentiated pleomorphic sarcoma in children and young adults: A comprehensive clinicopathologic, genomic, and epigenetic comparison with adult counterparts
Abstract:	Undifferentiated pleomorphic sarcoma (UPS) occurs primarily in older adults and remains a diagnosis of exclusion due to its lack of differentiation and specific molecular alterations. Its occurrence in children is rare and controversial, with an unclear relationship to its adult counterpart. In this study, we aimed to investigate a cohort of 6 pediatric undifferentiated pleomorphic sarcoma (P-UPS, mean 10 years old) and 19 young-adult undifferentiated pleomorphic sarcoma (YA-UPS, mean 30 years old) cases by conducting a comprehensive comparative analysis of their clinicopathologic, genomic, and epigenetic features relative to their adult undifferentiated pleomorphic sarcoma counterparts (A-UPS, n = 100). Histologically, P-UPS and YA-UPS exhibited broad morphologic spectrum. The most frequent alterations across all groups were TP53, CDKN2A/B, and ATRX, with no significant differences among subsets. Notably, RB1 alterations were absent in P-UPS, although representing the second most common alteration in YA-UPS (32%) and A-UPS (41%). PTEN alterations were significantly more prevalent in YA-UPS (26%) compared with that in P-UPS (0%) and A-UPS (6%). Deletions in chromosomes 10, 16q, and 13q, along with amplification of 20q, were the most common across all groups. Except for a higher frequency of 17q amplification in P-UPS (33%) and YA-UPS (26%) compared with that in A-UPS (6%), no other arm-level differences were observed. P-UPS showed a lower mean fraction genome altered compared with YA-UPS and A-UPS, whereas all UPS age groups showed a low tumor mutational burden (mean <10 mut/MB). Pathogenic germline variants of high clinical significance (TP53, NF1, MLH1, CHEK2, and BARD1) were observed only in YA-UPS (31%) and A-UPS (12%) cases. By T-distributed stochastic neighborhood embedding and hierarchical clustering of DNA methylation, the majority of P-UPS and a small subset of YA-UPS grouped in a distinct cluster, characterized by a lower genomic index compared to A-UPS. In contrast, most UPS occurring in young adults genomically parallel their older adults’ counterparts. P-UPS and YA-UPS cases exhibited a better disease-specific and progression-free survival, compared with A-UPS cases. © 2025 United States & Canadian Academy of Pathology
Keywords:	adolescent; adult; cancer survival; child; controlled study; human tissue; preschool child; cancer surgery; young adult; major clinical study; single nucleotide polymorphism; doxorubicin; gemcitabine; cancer radiotherapy; gene; progression free survival; tumor volume; cohort analysis; protein p53; dna methylation; distant metastasis; ifosfamide; docetaxel; sarcoma; fluorescence in situ hybridization; epigenetics; microsatellite instability; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; genomics; protein s 100; immunophenotyping; genome; checkpoint kinase 2; cyclin dependent kinase inhibitor 2a; children; transcriptome; disease specific survival; genomic dna; chromosome 16q; chromosome 17q; cyclin dependent kinase 4; chromosome 20q; ifosfamide plus mesna; smooth muscle actin; chromosome 13q; chromosome 10; cyclin dependent kinase inhibitor 2b; brca1 associated ring domain protein 1; young adults; dna hybridization; genomic; brm protein; brg1 protein; rb1 gene; transcription factor sox10; undifferentiated pleomorphic sarcoma; human; male; female; article; whole genome sequencing; rna sequencing; pembrolizumab; hierarchical clustering; mutl protein homolog 1; swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 1; transcriptional regulator atrx; tumor mutational burden; platelet endothelial cell adhesion molecule 1; epacadostat; mouse double minute 2 homolog; cytotoxic necrotizing factor 1
Journal Title:	Modern Pathology
Volume:	38
Issue:	8
ISSN:	0893-3952
Publisher:	Nature Research
Date Published:	2025-08-01
Start Page:	100769
Language:	English
DOI:	10.1016/j.modpat.2025.100769
PUBMED:	40222653
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105004642294&doi=10.1016%2fj.modpat.2025.100769&partnerID=40&md5=64b5a387bcdc1674da7f755d54be469d
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Cristina Antonescu -- Source: Scopus