Recently, FN1 fusions to receptor tyrosine kinase genes have been identified in soft tissue tumors with calcified chondroid matrix named calcifying chondroid mesenchymal neoplasms (CCMNs). We collected 33 cases of CCMN from the French network for soft tissue and bone tumors. We performed whole-exome RNA sequencing, expression analysis, and genome-wide DNA methylation profiling in 33, 30, and 20 cases of CCMN compared with a control group of tumors, including noncalcified tenosynovial giant cell tumor (TGCT). Among them, 15 cases showed morphologic overlap with soft tissue chondroma, 8 cases with tophaceous pseudogout, and 10 cases with chondroid TGCT. RNA-sequencing revealed a fusion of FN1 in 76% of cases (25/33) with different 5' partners, including most frequently FGFR2 (14 cases), TEK or FGFR1. Among CCMN associated with FGFR1 fusions, 2 cases had overexpression of FGF23 without tumor-induced osteomalacia. Four CCMN had PDGFRA::USP8 fusions; 3 of which had histologic features of TGCT and were located in the hip, foot, and temporomandibular joint (TMJ). All cases with FN1::TEK fusion were located at TMJ and had histologic features of TGCT with or without chondroid matrix. They formed a distinct cluster on unsupervised clustering analyses based on whole transcriptome and genome-wide methylome data. Our study confirms the high prevalence of FN1 fusions in CCMN. In addition, through transcriptome and methylome analyses, we have identified a novel subgroup of tumors located at the TMJ, exhibiting TGCT-like features and FN1::TEK fusions.

中文翻译：

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一系列钙化软骨样间质肿瘤的全面分子表征，拓宽了其形态谱。


最近，在具有钙化软骨样基质的软组织肿瘤中发现了 FN1 与受体酪氨酸激酶基因的融合，称为钙化软骨样间质肿瘤 (CCMN)。我们从法国软组织和骨肿瘤网络收集了 33 例 CCMN 病例。我们对 33、30 和 20 例 CCMN 病例进行了全外显子组 RNA 测序、表达分析和全基因组 DNA 甲基化分析，并与对照组肿瘤（包括非钙化腱鞘巨细胞瘤 (TGCT)）进行比较。其中软组织软骨瘤形态重叠15例，痛风石性假痛风8例，软骨样TGCT 10例。 RNA 测序显示，76% 的病例 (25/33) 存在 FN1 与不同 5' 伴侣的融合，包括最常见的 FGFR2（14 例）、TEK 或 FGFR1。与FGFR1融合相关的CCMN中，2例存在FGF23过度表达，但无肿瘤诱导的骨软化。四个 CCMN 具有 PDGFRA::USP8 融合；其中 3 个具有 TGCT 组织学特征，位于髋部、足部和颞下颌关节 (TMJ)。所有 FN1::TEK 融合的病例均位于 TMJ，并具有 TGCT 的组织学特征，有或没有软骨样基质。他们根据全转录组和全基因组甲基化数据进行无监督聚类分析，形成了一个独特的聚类。我们的研究证实了 CCMN 中 FN1 融合的高发生率。此外，通过转录组和甲基化组分析，我们发现了位于颞下颌关节的新肿瘤亚组，表现出类似 TGCT 的特征和 FN1::TEK 融合。