Journal Article

DKFZ-2026-01797

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrated Clinicopathological and Multiomic Profiling Reveals MEIS1-rearranged Sarcoma as a Distinct Entity with Two Prognostic Subgroups.

Yeung, M. C. F. ; Ip, P. P. C. ; Bennett, J. A. ; Lee, J.-C. ; Nam, M. H. ; Fontanges, Q. ; Tessier-Cloutier, B. ; Niu, S. ; Xing, D. ; Quiroga-Garza, G. M. ; John, I. ; von Deimling, A.DKFZ* ; Demicco, E. G. ; Dickson, B. C. ; Antonescu, C. R. ; Croce, S. ; Kommoss, F. K. F.

2026
Nature Publishing Group London

Abstract: Sarcomas with MEIS1 fusions represent a rare, recently recognized group of mesenchymal neoplasms with a predilection for genitourinary and gynecologic sites. A subset exhibits skeletal muscle differentiation resembling spindle cell rhabdomyosarcoma. Existing literature is limited to case reports and small series, with scant comprehensive clinicopathologic, molecular, and outcome data. In this study, we analyzed a multi-institutional cohort of 20 MEIS1-rearranged sarcomas using integrated clinicopathologic review, genomic profiling, and DNA methylation analysis. The tumors occurred in 17 females and 3 males (median age 41 years, range 6-58), arising mainly in the uterus/vagina (n=12), vulva/perineum (n=4), bone (n=2), and kidney (n=2), with a median size of 9 cm (range 2.5-20 cm). Histology showed mostly bland spindle cells in fascicles/storiform patterns, alternating cellularity, fibromyxoid stroma, prominent vascularity, and adipose metaplasia (45%). A subset of cases featured high-grade morphology with epithelioid cells and increased mitotic activity. Skeletal muscle markers were variably positive in 9 cases. Fusions involved MEIS1 with NCOA2 (16/20), NCOA1 (3/20), or FOXO1 (1/20). Recurrent additional genomic alterations included CTNNB1 mutations (31.6%) and MDM2 amplification (15%). DNA methylation profiling showed that MEIS1-rearranged sarcomas formed a unifying cluster comprising two subgroups, regardless of rhabdomyosarcomatous phenotype, clearly separated from other mesenchymal neoplasms, including various rhabdomyosarcoma subtypes and uterine sarcomas. The two DNA methylation subgroups correlated with differences in genome-wide copy-number variation status (Meth-CNVh vs Meth-CNVl), with Meth-CNVh tumors characterized by high mitotic rate, frequent tumor necrosis, recurrent co-occurring CTNNB1 and MDM2 alterations, and recurrent chromosomal arm-level changes. Most importantly, this subgroup exhibited significantly worse overall survival (median 25 vs 44.5 months; p=0.027) and disease-free survival (5 vs 28 months; p=0.017). This study establishes MEIS1-rearranged sarcoma as a distinct entity with generally indolent but potentially aggressive behavior. The two methylation/CNV subgroups provide potential utility for prognostic stratification and highlight actionable molecular targets in high-risk cases.

Keyword(s): MEIS1 ; Methylation ; Molecular ; Multiomics ; NCOA1/2 ; Sarcoma

Note: #DKTKZFB26# / epub

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Contributing Institute(s):

1. KKE Neuropathologie (B300)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Springer ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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