Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature

Christian Koelsche,Jamal K Benhamida,Felix K.F Kommoss,Damian Stichel,David T.W Jones,Stefan M Pfister,Christoph E Heilig,Stefan Fröhling,Albrecht Stenzinger,Rolf Buslei,Thomas Mentzel,Daniel Baumhoer,Marc Ladanyi,Cristina R Antonescu,Uta Flucke,Joost Van Gorp,Beata Bode-Lesniewska,Andreas Von Deimling,Gunhild Mechtersheimer

doi:10.1038/s41379-021-00874-y

Abstract

Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This “ISA” methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification.

Highlights

Intimal sarcoma (ISA) is an exceedingly rare undifferentiated sarcoma that arises in the pulmonary artery and less frequently in the aorta or its branches [1]
Study cohort and histopathology The study included 25 cases with ISAs arising in the pulmonary artery and one case with an ISA of the renal artery
In this study we assessed the molecular profiles of ISAs and undifferentiated pleomorphic sarcomas (UPS) of the left atrium using genome-wide copy number profiling and unsupervised DNA methylation analysis

Summary

Introduction

Intimal sarcoma (ISA) is an exceedingly rare undifferentiated sarcoma that arises in the pulmonary artery and less frequently in the aorta or its branches [1]. Patients with ISA are mostly of middle age at diagnosis and typically present with non-specific symptoms, which sometimes masquerades as thromboembolic disease. Patients are often diagnosed in an advanced disease stage. ISAs are often reported to be resistant to conventional chemotherapy [2]. First recognized by Mandelstamm as pulmonary artery sarcoma from an autopsy in 1923, case reports and small case series have been published for the following decades [3]. The term “intimal” was coined with reference to the attributes that these sarcomas arise from the subendothelial space of arteries, form polypoidal and endoluminal protrusions and spread laterally along the intima

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Conclusion