纤维瘤病的基因谱分析显示染色质重塑基因频繁突变，并识别出一种免疫-肌源性亚型

We performed integrated genomic, transcriptomic, and DNA methylation profiling on 76 DTs, including post-treatment samples. Targeted gene panel sequencing, RNA-seq, and EPIC methylation arrays were conducted. Molecular subtypes were validated in external cohorts, and immunotherapy response was predicted using immune deconvolution and TIDE analysis.

Beyond canonical CTNNB1/APC mutations, we discovered frequent mutations in chromatin-remodeling genes, notably KMT2C (18%), found in over 50% of samples, including in wild-type tumors. Unsupervised transcriptomic analysis revealed two robust molecular subtypes: immune-myogenic and mesenchymal-like. The immune-myogenic subtype exhibited high expression of myogenic markers, immune checkpoint genes (PDCD1, CD274, CTLA4), tertiary lymphoid structure signatures, and global enhancer hypomethylation linked to interferon and myogenesis pathways. It showed increased infiltration of T, B, and NK cells, higher vascularization, and elevated stemness and epithelial-mesenchymal transition plasticity. TIDE analysis predicted significantly higher ICI responsiveness in the immune-myogenic subtype (58% vs. 26%, p = 0.008), confirmed in an external cohort (69% vs. 10%, p < 0.001). Transcriptomic profiles were stable across intra-tumoral regions, supporting subtype robustness.

This study expands the genomic understanding of DTs by uncovering frequent epigenetic regulator mutations and identifying an immune-myogenic subtype with immunogenic and plastic features. These findings support immunotherapeutic strategies in selected DT patients and emphasize the importance of integrated molecular profiling.