BACKGROUND Intimal sarcoma is a rare and aggressive soft-tissue sarcoma with limited treatment options. We explored genomic profiles of intimal sarcoma to uncover therapeutic implications.

MATERIALS AND METHODS We analyzed tumor tissues from patients with intimal sarcoma who visited the Seoul National University Hospital (SNUH) using whole-exome, whole-transcriptome, and clinical next-generation sequencing (NGS), integrated with intimal sarcoma NGS data from two public cohorts. We examined expression characteristics and tumor-infiltrating lymphocytes (TILs) according to molecular subtypes.

RESULTS Our study included 42 samples in total. Thirty-three patients showing copy number variation (CNV) enrichment with frequent CDK4/MDM2 amplifications were classified as the CNV-high (CNV-H) subtype. Five patients showing predominant MLH1 mutations or homozygous deletions were classified as the microsatellite instability-high-like (MSI-H-like) subtype. Hallmark pathways up-regulated in the CNV-H subtype included Wnt β-catenin and Hedgehog signaling. In the MSI-H-like subtype, interferon-γ response, tumor necrosis factor-α signaling via nuclear factor-κB, interferon-α response, inflammatory response, and interleukin-6-Jak-Stat3 signaling were up-regulated. CNV-H subtype samples predominantly showed an immune-desert phenotype, whereas MSI-H-like subtype samples predominantly showed an immune-inflamed phenotype. Two MSI-H-like subtype patients received pembrolizumab and experienced tumor shrinkage.

CONCLUSIONS We identified two intimal sarcoma molecular subtypes. Compared with CNV-H, MSI-H-like is enriched in pathways associated with tumor immune responses and TILs. Further efforts and clinical trials to better define these molecular subtypes are warranted to open new avenues for personalized treatment approaches and improve patient outcomes.