Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Pediatrics, Brussels University Hospital, Academic Children's Hospital Queen Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
Genes Chromosomes Cancer. 2024 Apr;63(4):e23232. doi: 10.1002/gcc.23232.
The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.
RNA 测序在临床实践中的广泛应用使得新型融合基因得以发现，这有助于对横纹肌肉瘤（RMS）进行更精细的分子分类。RMS 中的大多数融合导致异常转录因子，例如肺泡 RMS（ARMS）中的 PAX3/7::FOXO1 和涉及 VGLL2 或 NCOA2 的婴儿梭形细胞 RMS。然而，在 RMS 中尚未报道导致致癌激酶激活的复发性融合。在一个未分类的 RMS（ARMS 和硬化 RMS 之间存在重叠特征）的索引病例（具有新型 FGFR1::ANK1 融合）的触发下，我们回顾了我们的分子档案，以寻找携带 FGFR1 相关融合的病例。在一个具有间变性、但在胚系检测中没有 TP53 或 DICER1 致病性变异的胚胎样 RMS（ERMS）样肿瘤中，鉴定出了另一个 FGFR1::TACC1 融合病例。这两个病例均发生在男性，年龄分别为 7 岁和 24 岁，且均位于骨盆。第二个病例还存在其他改变，包括体细胞 TP53 和 TET2 突变。通过 RNA 测序鉴定出另外两个 RMS 病例（一个未分类，一个 ERMS），这些病例 FGFR1 过表达但缺乏 FGFR1 融合。这两个病例和 FGFR1::TACC1 阳性病例通过 RNAseq 与 ERMS 组聚类在一起。这是 RMS 中存在复发性 FGFR1 融合的首次报道。然而，目前尚不清楚 FGFR1 融合是否定义了 RMS 的一个新亚组，或者这种改变是否可以偶然驱动已知 RMS 亚型（如 ERMS）的发病机制。需要更大的、具有整合基因组和表观遗传数据集的系列研究来进行更好的亚分类，因为由此产生的致癌激酶激活强调了靶向治疗的潜力。
